Pyridine-and pyrazine derivatives

ABSTRACT

Compounds of the formula (I) in which R, R 1  and X have the meanings indicated in claim  1 , are inhibitors of TBK1 and IKKε and can be employed, inter alia, for the treatment of cancer and inflammatory diseases

BACKGROUND OF THE INVENTION

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

The present invention relates to pyridine compounds that are capable ofinhibiting one or more kinases. The compounds find applications in thetreatment of a variety of disorders, including cancer, septic shock,Primary open Angle Glaucoma (POAG), hyperplasia, rheumatoid arthritis,psoriasis, artherosclerosis, retinopathy, osteoarthritis, endometriosis,chronic inflammation, and/or neurodegenerative diseases such asAlzheimers disease.

The present invention relates to compounds and to the use of compoundsin which the inhibition, regulation and/or modulation of signaltransduction by kinases, in particular receptor tyrosine kinases,furthermore to pharmaceutical compositions which comprise thesecompounds, and to the use of the compounds for the treatment ofkinase-induced diseases.

Because protein kinases regulate nearly every cellular process,including metabolism, cell proliferation, cell differentiation, and cellsurvival, they are attractive targets for therapeutic intervention forvarious disease states. For example, cell-cycle control andangiogenesis, in which protein kinases play a pivotal role are cellularprocesses associated with numerous disease conditions such as but notlimited to cancer, inflammatory diseases, abnormal angiogenesis anddiseases related thereto, atherosclerosis, macular degeneration,diabetes, obesity, and pain.

In particular, the present invention relates to compounds and to the useof compounds in which the inhibition, regulation and/or modulation ofsignal transduction by TBK1 and IKKε plays a role.

One of the principal mechanisms by which cellular regulation is effectedis through the transduction of extracellular signals across the membranethat in turn modulate biochemical pathways within the cell. Proteinphosphorylation represents one course by which intracellular signals arepropagated from molecule to molecule resulting finally in a cellularresponse. These signal transduction cascades are highly regulated andoften overlap, as is evident from the existence of many protein kinasesas well as phosphatases. Phosphorylation of proteins occurspredominantly at serine, threonine or tyrosine residues, and proteinkinases have therefore been classified by their specificity ofphosphorylation site, i.e. serine/threonine kinases and tyrosinekinases. Since phosphorylation is such a ubiquitous process within cellsand since cellular phenotypes are largely influenced by the activity ofthese pathways, it is currently believed that a number of disease statesand/or diseases are attributable to either aberrant activation orfunctional mutations in the molecular components of kinase cascades.Consequently, considerable attention has been devoted to thecharacterisation of these proteins and compounds that are able tomodulate their activity (for a review see: Weinstein-Oppenheimer et al.Pharma. &. Therap., 2000, 88, 229-279).

IKKε and TBK1 are serine/threonine kinases which are highly homologousto one another and to other IkB kinases. The two kinases play anintegral role in the innate immune system. Double-stranded RNA virusesare recognised by the Toll-like receptors 3 and 4 and the RNA helicasesRIG-I and MDA-5 and result in activation of the TRIF-TBK1/IKKe-IRF3signalling cascade, which results in a type I interferon response.

In 2007, Boehm et al. described IKKε as a novel breast cancer oncogene[J. S. Boehm et al., Cell 129, 1065-1079, 2007]. 354 kinases wereinvestigated with respect to their ability to recapitulate theRas-transforming phenotype together with an activated form of the MAPKkinase Mek. IKKε was identified here as a cooperative oncogene. Inaddition, the authors were able to show that IKKε is amplified andoverexpressed in numerous breast cancer cell lines and tumour samples.The reduction in gene expression by means of RNA interference in breastcancer cells induces apoptosis and impairs the proliferation thereof.Eddy et al. obtained similar findings in 2005, which underlines theimportance of IKKε in breast cancer diseases [S. F. Eddy et al., CancerRes. 2005; 65 (24), 11375-11383].

A protumorigenic effect of TBK1 was reported for the first time in 2006.In a screening of a gene library comprising 251,000 cDNA, Korherr et al.identified precisely three genes, TRIF, TBK1 and IRF3, which aretypically involved in the innate immune defense as proangiogenic factors[C. Korherr et al., PNAS, 103, 4240-4245, 2006]. In 2006, Chien et al.[Y. Chien et al., Cell 127, 157-170, 2006] published that TBK1−/− cellscan only be transformed to a limited extent using oncogenic Ras, whichsuggests an involvement of TBK1 in the Ras-mediated transformation.Furthermore, they were able to show that an RNAi-mediated knock-down ofTBK1 triggers apoptosis in MCF-7 and Panc-1 cells. Barbie et al.recently published that TBK1 is of essential importance in numerouscancer cell lines with mutated K-Ras, which suggests that TBK1intervention could be of therapeutic importance in corresponding tumours[D. A. Barbie et al., Nature Letters 1-5, 2009].

Diseases caused by protein kinases are characterised by anomalousactivity or hyperactivity of such protein kinases. Anomalous activityrelates to either: (1) expression in cells which do not usually expressthese protein kinases; (2) increased kinase expression, which results inundesired cell proliferation, such as cancer; (3) increased kinaseactivity, which results in undesired cell proliferation, such as cancer,and/or in hyperactivity of the corresponding protein kinases.Hyperactivity relates either to amplification of the gene which encodesfor a certain protein kinase, or the generation of an activity levelwhich can be correlated with a cell proliferation disease (i.e. theseverity of one or more symptoms of the cell proliferation diseaseincreases with increasing kinase level). The bioavailability of aprotein kinase may also be influenced by the presence or absence of aset of binding proteins of this kinase.

IKKε and TBK1 are highly homologous Ser/Thr kinases critically involvedin the innate immune response through induction of type 1 interferonsand other cytokines. These kinases are stimulated in response toviral/bacterial infection. Immune response to viral and bacterialinfection involves the binding of antigens such as bacteriallipopolysaccharide (LPS), viral doublestranded RNS (dsRNA) to Toll likereceptors, then subsequent activation of TBK1 pathway. Activated TBK1and IKKε phosphorylate IRF3 and IRF7, which triggers the dimerizationand nuclear translocation of those interferon regulatory transcriptionfactors, ultimately inducing a signaling cascades leading to IFNproduction.

Recently, IKKε and TBK1 have also been implicated in cancer. It has beenshown that IKKε cooperates with activated MEK to transform human cells.In addition, IKKε is frequently amplified/overexpressed in breast cancercell lines and patient-derived tumors. TBK1 is induced under hypoxicconditions and expressed at significant levels in many solid tumors.

Furthermore, TBK1 is required to support oncogenic Ras transformation,and TBK1 kinase activity is elevated in transformed cells and requiredfor their survival in culture. Similarly, it was found that TBK1 andNF-kB signalling are essential in KRAS mutant tumors. They haveidentified TBK1 as a synthetic lethal partner of oncogenic KRAS. Lit.:

-   Y. H. Ou et al., Molecular Cell 41, 458-470, 2011;-   D. A. Barbie et al., nature, 1-5, 2009.

Accordingly, the compounds according to the invention or apharmaceutically acceptable salt thereof are administered for thetreatment of cancer, including solid carcinomas, such as, for example,carcinomas (for example of the lungs, pancreas, thyroid, bladder orcolon), myeloid diseases (for example myeloid leukaemia) or adenomas(for example villous colon adenoma).

The tumours furthermore include monocytic leukaemia, brain, urogenital,lymphatic system, stomach, laryngeal and lung carcinoma, including lungadenocarcinoma and small-cell lung carcinoma, pancreatic and/or breastcarcinoma.

The compounds are furthermore suitable for the treatment of immunedeficiency induced by HIV-1 (Human Immunodeficiency Virus Type 1).

Cancer-like hyperproliferative diseases are to be regarded as braincancer, lung cancer, squamous epithelial cancer, bladder cancer, stomachcancer, pancreatic cancer, liver cancer, renal cancer, colorectalcancer, breast cancer, head cancer, neck cancer, oesophageal cancer,gynaecological cancer, thyroid cancer, lymphomas, chronic leukaemia andacute leukaemia. In particular, cancer-like cell growth is a diseasewhich represents a target of the present invention. The presentinvention therefore relates to compounds according to the invention asmedicaments and/or medicament active ingredients in the treatment and/orprophylaxis of the said diseases and to the use of compounds accordingto the invention for the preparation of a pharmaceutical for thetreatment and/or prophylaxis of the said diseases and to a process forthe treatment of the said diseases comprising the administration of oneor more compounds according to the invention to a patient in need ofsuch an administration.

It can be shown that the compounds according to the invention have anantiproliferative action. The compounds according to the invention areadministered to a patient having a hyperproliferative disease, forexample to inhibit tumour growth, to reduce inflammation associated witha lymphoproliferative disease, to inhibit transplant rejection orneurological damage due to tissue repair, etc. The present compounds aresuitable for prophylactic or therapeutic purposes. As used herein, theterm “treatment” is used to refer to both the prevention of diseases andthe treatment of pre-existing conditions. The prevention ofproliferation/vitality is achieved by administration of the compoundsaccording to the invention prior to the development of overt disease,for example for preventing tumour growth. Alternatively, the compoundsare used for the treatment of ongoing diseases by stabilising orimproving the clinical symptoms of the patient.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of a human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro testing.Typically, a culture of the cell is incubated with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to induce cell death or to inhibitcell proliferation, cell vitality or migration, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from a biopsy sample. The amount of cells remainingafter the treatment are then determined. The dose varies depending onthe specific compound used, the specific disease, the patient status,etc. A therapeutic dose is typically sufficient considerably to reducethe undesired cell population in the target tissue, while the viabilityof the patient is maintained. The treatment is generally continued untila considerable reduction has occurred, for example an at least about 50%reduction in the cell burden, and may be continued until essentially nomore undesired cells are detected in the body.

There are many diseases associated with deregulation of cellproliferation and cell death (apoptosis). The conditions of interestinclude, but are not limited to, the following. The compounds accordingto the invention are suitable for the treatment of various conditionswhere there is proliferation and/or migration of smooth muscle cellsand/or inflammatory cells into the intimal layer of a vessel, resultingin restricted blood flow through that vessel, for example in the case ofneointimal occlusive lesions. Occlusive graft vascular diseases ofinterest include atherosclerosis, coronary vascular disease aftergrafting, vein graft stenosis, perianastomatic prosthetic restenosis,restenosis after angioplasty or stent placement, and the like.

In addition, the compounds according to the invention can be used toachieve additive or synergistic effects in certain existing cancerchemotherapies and radiotherapies and/or to restore the efficacy ofcertain existing cancer chemotherapies and radiotherapies.

The term “method” refers to manners, means, techniques and proceduresfor accomplishing a given task including, but not limited to, thosemanners, means, techniques and procedures either known to, or readilydeveloped from known manners, means, techniques and procedures bypractitioners of the chemical, pharmacological, biological, biochemicaland medical arts.

The term “administering” as used herein refers to a method for bringinga compound of the present invention and a target kinase together in sucha manner that the compound can affect the enzyme activity of the kinaseeither directly; i.e., by interacting with the kinase itself orindirectly; i.e., by interacting with another molecule on which thecatalytic activity of the kinase is dependent. As used herein,administration can be accomplished either in vitro, i.e. in a test tube,or in vivo, i.e., in cells or tissues of a living organism.

Herein, the term “treating” includes abrogating, substantiallyinhibiting, slowing or reversing the progression of a disease ordisorder, substantially ameliorating clinical symptoms of a disease ordisorder or substantially preventing the appearance of clinical symptomsof a disease or disorder.

Herein, the term “preventing” refers to a method for barring an organismfrom acquiring a disorder or disease in the first place.

For any compound used in this invention, a therapeutically effectiveamount, also referred to herein as a therapeutically effective dose, canbe estimated initially from cell culture assays. For example, a dose canbe formulated in animal models to achieve a circulating concentrationrange that includes the IC50 or the IC100 as determined in cell culture.Such information can be used to more accurately determine useful dosesin humans. Initial dosages can also be estimated from in vivo data.Using these initial guidelines one of ordinary skill in the art coulddetermine an effective dosage in humans.

Moreover, toxicity and therapeutic efficacy of the compounds describedherein can be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., by determining the LD50 and theED50. The dose ratio between toxic and therapeutic effect is thetherapeutic index and can be expressed as the ratio between LD50 andED50. Compounds which exhibit high therapeutic indices are preferred.The data obtained from these cell cultures assays and animal studies canbe used in formulating a dosage range that is not toxic for use inhuman. The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED50 with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition, (see, e.g.,Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics,chapter 1, page 1).

Dosage amount and interval may be adjusted individually to provideplasma levels of the active compound which are sufficient to maintaintherapeutic effect. Usual patient dosages for oral administration rangefrom about 50-2000 mg/kg/day, commonly from about 100-1000 mg/kg/day,preferably from about 150-700 mg/kg/day and most preferably from about250-500 mg/kg/day.

Preferably, therapeutically effective serum levels will be achieved byadministering multiple doses each day. In cases of local administrationor selective uptake, the effective local concentration of the drug maynot be related to plasma concentration. One skilled in the art will beable to optimize therapeutically effective local dosages without undueexperimentation.

Preferred diseases or disorders that the compounds described herein maybe useful in preventing, treating and/or studying are cell proliferativedisorders, especially cancer such as, but not limited to, papilloma,blastoglioma, Kaposi's sarcoma, melanoma, lung cancer, ovarian cancer,prostate cancer, squamous cell carcinoma, astrocytoma, head cancer, neckcancer, skin cancer, liver cancer, bladder cancer, breast cancer, lungcancer, uterus cancer, prostate cancer, testis carcinoma, colorectalcancer, thyroid cancer, pancreatic cancer, gastric cancer,hepatocellular carcinoma, leukemia, lymphoma, Hodgkin's disease andBurkitt's disease.

PRIOR ART

Other heterocyclic derivatives and their use as anti-tumour agents havebeen described in WO 2007/129044.

Other pyridine and pyrazine derivatives have been described in the usefor the treatment of cancer in WO 2009/053737 and for the treatment ofother diseases in WO 2004/055005.

Other heterocyclic derivatives have been disclosed as IKKε inhibitors inWO 2009/122180.

Pyrrolopyrimidines have been describes as IKKε and TBK1 inhibitors in WO2010/100431.

Pyrimidine derivatives have been describes as IKKε and TBK1 inhibitorsin WO 2009/030890.

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula I

in which

-   X denotes CH or N,-   R denotes Ar or Het,-   R¹ denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazinyl,    indolyl, isoindolyl, benzimidazolyl, indazolyl, quinolyl,    1,3-benzodioxolyl, benzothiophenyl, benzofuranyl, imidazopyridyl or    furo[3,2-b]pyridyl, each of which is unsubstituted or mono- or    disubstituted by Hal, A, OR⁵, CN, COOA, COOH, CON(R⁵)₂ and/or    NR⁵COA′,-   Ar denotes phenyl, biphenyl or naphtyl, each of which is    unsubstituted or mono-, di- or trisubstituted by Hal, A, Het¹,    (CH₂)_(n)OR⁵, (CH₂)_(n)N(R⁵)₂, NO₂, CN, (CH₂)_(n)COOR⁵, CON(R⁵)₂,    CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NR⁵COA, NHCOOA, NR⁵SO₂A,    COR⁵, SO₂Het², SO₂N(R⁵)₂ and/or S(O)_(p)A,-   Het denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl,    tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl, indolyl,    isoindolyl, benzimidazolyl, indazolyl, quinolyl, 1,3-benzodioxolyl,    benzothiophenyl, benzofuranyl or imidazopyridyl, each of which is    unsubstituted or mono-, di- or trisubstituted by A, COA,    (CH₂)_(p)Het², OH, OA, Hal, (CH₂)_(p)N(R⁵)₂, NO₂, CN,    (CH₂)_(p)COOR⁵, (CH₂)_(p)CON(R⁵)₂, NR⁵COA, (CH₂)_(p)COHet² and/or    (CH₂)_(p)phenyl,-   Het¹ denotes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,    oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, triazolyl,    tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl, each of which is    unsubstituted or mono-, di- or trisubstituted by A, OH, OA, Hal, CN    and/or (CH₂)_(p)COOR⁵,-   Het² denotes dihydropyrrolyl, pyrrolidinyl, tetrahydroimidazolyl,    dihydropyrazolyl, tetrahydropyrazolyl, dihydropyridyl,    tetrahydropyridyl, piperidinyl, morpholinyl, hexahydropyridazinyl,    hexahydropyrimidinyl, [1,3]dioxolanyl, piperazinyl, each of which is    unsubstituted or monosubstituted by OH and/or A,-   A′ denotes unbranched or branched alkyl having 1-6 C atoms, in which    1-7 H atoms may be replaced by F,-   A denotes unbranched or branched alkyl having 1-10 C atoms, in which    one or two non-adjacent CH and/or CH₂ groups may be replaced by N,    O, S atoms and/or by —CH═CH— groups and/or in addition 1-7 H atoms    may be replaced by F,-   R⁵ denotes H or unbranched or branched alkyl having 1-6 C atoms, in    which 1-7 H atoms may be replaced by F,-   Hal denotes F, Cl, Br or I,-   n denotes 0, 1, 2, 3 or 4,-   p denotes 0, 1 or 2,-   q denotes 1, 2, 3 or 4,    and pharmaceutically usable salts, tautomers and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), salts, the enantiomers, the racemates, thediastereomers and the hydrates and solvates of these compounds. The termsolvates of the compounds is taken to mean adductions of inert solventmolecules onto the compounds which form owing to their mutual attractiveforce. Solvates are, for example, mono- or dihydrates or alkoxides. Ofcourse, the invention also relates to the solvates of the salts.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds. The term prodrug derivatives is taken tomean compounds of the formula I which have been modified by means of,for example, alkyl or acyl groups, sugars or oligopeptides and which arerapidly cleaved in the organism to form the effective compoundsaccording to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side effects or also thereduction in the advance of a disease, condition or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI according to claims 1-12 and pharmaceutically usable salts, tautomersand stereoisomers thereof, characterised in that

-   a) a compound of the formula II

-   in which Y denotes an Br or I,-   X and R¹ have the meanings indicated in Claim 1,-   is reacted with a compound of formula III    R-L  III-   in which R has the meaning indicated in Claim1 and-   L denotes a boronic acid or a boronic acid ester group,-   or-   b) a compound of the formula IV

-   in which R and X have the meanings indicated in Claim 1 and-   L¹ denotes Cl, Br, I or a free or reactively functionally modified    OH group,-   is reacted with a compound of the formula V    R¹—NH₂  V-   in which R¹ has the meaning indicated in Claim 1,-   or-   c) that it is liberated from one of its functional derivatives by    treatment with a solvolysing or hydrolysing agent,-   and/or a base or acid of the formula I is converted into one of its    salts.

Above and below, the radicals R¹, R and X have the meanings indicatedfor the formula I, unless expressly indicated otherwise.

A denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl, furthermoreethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl,furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl.

One or two CH and/or CH₂ groups in A may also be replaced by N, O or Satoms and/or by —CH═CH— groups. A thus also denotes, for example,2-methoxyethyl. More preferably, A denotes unbranched or branched alkylhaving 1-6 C atoms, in which one or two non-adjacent CH and/or CH₂groups may be replaced by N and/or O atoms and/or in addition 1-7 Hatoms may be replaced by F.

A′ denotes alkyl, is unbranched (linear) or branched, and has 1, 2, 3,4, 5 or 6 C atoms. A preferably denotes methyl, furthermore ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermorealso pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, further preferably, for example, trifluoromethyl.

A′ preferably denotes alkyl having 1, 2, 3 or 4 C atoms, preferablymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butylor trifluoromethyl.

Ar denotes, for example, phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-trifluoromethylphenyl, o-, m-or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl,o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- orp-methylsulfonylphenyl, o-, m- or p-nitrophenyl, o-, m- orp-aminophenyl, o-, m- or p-methylaminophenyl, o-, m- orp-dimethylaminophenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-methylaminosulfonylphenyl, o-, m- or p-aminocarbonylphenyl, o-, m- orp-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-acetylphenyl, o-, m- orp-formylphenyl, o-, m- or p-cyanophenyl, further preferably 2,3-, 2,4-,2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, p-iodo-phenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar particularly preferably denotes phenyl, biphenyl or naphtyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂.

Het preferably denotes thienyl, pyrazolyl, pyridyl, each of which isunsubstituted or mono- or disubstituted by A, (CH₂)_(p)Het²,(CH₂)_(p)CON(R⁵)₂ and/or (CH₂)_(p)phenyl.

Het¹ preferably denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A.

Het² preferably denotes pyrrolidinyl, piperidinyl, morpholinyl,[1,3]dioxolanyl, piperazinyl, each of which is unsubstituted ormonosubstituted by OH and/or A.

R¹ preferably denotes pyridyl, pyrimidyl, pyridazinyl orfuro[3,2-b]pyridyl, each of which is unsubstituted or monosubstituted byHal, A, OR⁵, COOA, COOH, CON(R⁵)₂ and/or NR⁵COA′.

R⁵ preferably denotes H, alkyl having 1, 2, 3 or 4 C atoms, morepreferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl or trifluoromethyl.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ig, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R¹ denotes pyridyl, pyrimidyl, pyridazinyl or    furo[3,2-b]pyridyl, each of which is unsubstituted or    monosubstituted by Hal, A, OR⁵, COOA, COOH, CON(R⁵)₂ and/or NR⁵COA′;-   in Ib Ar denotes phenyl, biphenyl or naphtyl, each of which is    unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹, COR⁵,    CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,    (CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or    SO₂N(R⁵)₂;-   in Ic Het denotes thienyl, pyrazolyl, pyridyl, each of which is    unsubstituted or mono- or disubstituted by A, (CH₂)_(p)Het²,    (CH₂)_(p)CON(R⁵)₂ and/or (CH₂)_(p)phenyl;-   in Id Het¹ denotes pyrazolyl or imidazolyl, each of which is    unsubstituted or monosubstituted by A;-   in Ie Het² denotes pyrrolidinyl, piperidinyl, morpholinyl,    [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or    monosubstituted by OH and/or A;-   in If A denotes unbranched or branched alkyl having 1-6 C atoms, in    which one or two non-adjacent CH and/or CH₂ groups may be replaced    by N and/or O atoms and/or in addition 1-7 H atoms may be replaced    by F;-   in Ig X denotes CH oder N,    -   R denotes Ar or Het,    -   R¹ denotes pyridyl, pyrimidyl, pyridazinyl or        furo[3,2-b]pyridyl, each of which is unsubstituted or        monosubstituted by Hal, A, OR⁵, COOA, COOH, CON(R⁵)₂ and/or        NR⁵COA′,    -   Ar denotes phenyl, biphenyl or naphtyl, each of which is        unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,        COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹],        NHCOOA, (CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het²        and/or SO₂N(R⁵)₂,    -   Het denotes thienyl, pyrazolyl, pyridyl, each of which is        unsubstituted or mono- or disubstituted by A, (CH₂)_(p)Het²,        (CH₂)_(p)CON(R⁵)₂ and/or (CH₂)_(p)phenyl,    -   Het¹ denotes pyrazolyl or imidazolyl, each of which is        unsubstituted or monosubstituted by A,    -   Het² denotes pyrrolidinyl, piperidinyl, morpholinyl,        [1,3]dioxolanyl, piperazinyl, each of which is unsubstituted or        monosubstituted by OH and/or A,    -   A′ denotes unbranched or branched alkyl having 1-6 C atoms, in        which 1-7 H atoms may be replaced by F,    -   A denotes unbranched or branched alkyl having 1-6 C atoms, in        which one or two non-adjacent CH and/or CH₂ groups may be        replaced by N and/or O atoms and/or in addition 1-7 H atoms may        be replaced by F,    -   R⁵ denotes H or unbranched or branched alkyl having 1-6 C atoms,        in which 1-7 H atoms may be replaced by F,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 0, 1 or 2,    -   q denotes 1, 2, 3 or 4,        and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

Compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with a compound of formula III.

The compounds of the formula II and of formula III are generally known.If they are novel, however, they can be prepared by methods known perse.

The reaction is carried out under standard conditions known as Suzukireaction to the skilled artisan.

In the compounds of the formula III, L preferably denotes

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between 0° and 110°, in particular between about 60° andabout 110°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to ethanol, toluene, imethoxyethane,acetonitrile, dichloromethane, DMF and/or water.

Furthermore, compounds of the formula I can preferably be obtained byreacting a compound of the formula IV with a compound of the formula V.

The compounds of the formula IV and of formula V are generally known. Ifthey are novel, however, they can be prepared by methods known per se.

In the compounds of the formula IV, L¹ preferably denotes Cl, Br, I or afree or reactively modified OH group, such as, for example, an activatedester, an imidazolide or alkylsulfonyloxy having 1-6 C atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° and140°, normally between −10° and 90°, in particular between about 0° andabout 70°.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents.

Particular preference is given to acetonitrile, dichloromethane and/orDMF.

The cleavage of an ether is carried out by methods as are known to theperson skilled in the art.

A standard method of ether cleavage, for example of a methyl ether, isthe use of boron tribromide.

Hydrogenolytically removable groups, for example the cleavage of abenzyl ether, can be cleaved off, for example, by treatment withhydrogen in the presence of a catalyst (for example a noble-metalcatalyst, such as palladium, advantageously on a support, such ascarbon). Suitable solvents here are those indicated above, inparticular, for example, alcohols, such as methanol or ethanol, oramides, such as DMF. The hydrogenolysis is generally carried out attemperatures between about 0 and 100° and pressures between about 1 and200 bar, preferably at 20-30° and 1-10 bar.

Esters can be saponified, for example, using acetic acid or using NaOHor KOH in water, water/THF or water/dioxane, at temperatures between 0and 100°.

Alkylations on the nitrogen are carried out under standard conditions,as are known to the person skilled in the art.

The compounds of the formulae I can furthermore be obtained byliberating them from their functional derivatives by solvolysis, inparticular hydrolysis, or by hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which contain corresponding protected amino and/or hydroxyl groupsinstead of one or more free amino and/or hydroxyl groups, preferablythose which carry an amino-protecting group instead of an H atom bondedto an N atom, for example those which conform to the formula I, butcontain an NHR′ group (in which R′ denotes an amino-protecting group,for example BOC or CBZ) instead of an NH₂ group.

Preference is furthermore given to starting materials which carry ahydroxyl-protecting group instead of the H atom of a hydroxyl group, forexample those which conform to the formula I, but contain an R″O-phenylgroup (in which R″ denotes a hydroxyl-protecting group) instead of ahydroxyphenyl group.

It is also possible for a plurality of—identical or different—protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, they can in many cases be cleaved off selectively.

The expression “amino-protecting group” is known in general terms andrelates to groups which are suitable for protecting (blocking) an aminogroup against chemical reactions, but are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since theamino-protecting groups are removed after the desired reaction (orreaction sequence), their type and size is furthermore not crucial;however, preference is given to those having 1-20, in particular 1-8, Catoms. The expression “acyl group” is to be understood in the broadestsense in connection with the present process. It includes acyl groupsderived from aliphatic, araliphatic, aromatic or heterocyclic carboxylicacids or sulfonic acids, and, in particular, alkoxycarbonyl,aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of suchacyl groups are alkanoyl, such as acetyl, propionyl, butyryl;aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl, tolyl;aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl,ethoxycarbonyl, 2,2,2-tri-chloroethoxycarbonyl, BOC,2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ (“carbobenzoxy”),4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl, such as Mtr, Pbf, Pmc.Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ,Fmoc, benzyl and acetyl.

The expression “hydroxyl-protecting group” is likewise known in generalterms and relates to groups which are suitable for protecting a hydroxylgroup against chemical reactions, but are easy to remove after thedesired chemical reaction has been carried out elsewhere in themolecule. Typical of such groups are the above-mentioned unsubstitutedor substituted aryl, aralkyl or acyl groups, furthermore also alkylgroups. The nature and size of the hydroxyl-protecting groups is notcrucial since they are removed again after the desired chemical reactionor reaction sequence; preference is given to groups having 1-20, inparticular 1-10, C atoms. Examples of hydroxyl-protecting groups are,inter alia, tert-butoxycarbonyl, benzyl, p-nitrobenzoyl,p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butylare particularly preferred. The COOH groups in aspartic acid andglutamic acid are preferably protected in the form of their tert-butylesters (for example Asp(OBut)).

The compounds of the formula I are liberated from their functionalderivatives—depending on the protecting group used—for example usingstrong acids, advantageously using TFA or perchloric acid, but alsousing other strong inorganic acids, such as hydrochloric acid orsulfuric acid, strong organic carboxylic acids, such as trichloroaceticacid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. Thepresence of an additional inert solvent is possible, but is not alwaysnecessary. Suitable inert solvents are preferably organic, for examplecarboxylic acids, such as acetic acid, ethers, such as tetrahydrofuranor dioxane, amides, such as DMF, halogenated hydrocarbons, such asdichloromethane, furthermore also alcohols, such as methanol, ethanol orisopropanol, and water. Mixtures of the above-mentioned solvents arefurthermore suitable. TFA is preferably used in excess without additionof a further solvent, perchloric acid is preferably used in the form ofa mixture of acetic acid and 70% perchloric acid in the ratio 9:1. Thereaction temperatures for the cleavage are advantageously between about0 and about 50°, preferably between 15 and 30° (room temperature).

The BOC, OBut, Pbf, Pmc and Mtr groups can, for example, preferably becleaved off using TFA in dichloromethane or using approximately 3 to 5 NHCl in dioxane at 15-30°, the FMOC group can be cleaved off using anapproximately 5 to 50% solution of dimethylamine, diethylamine orpiperidine in DMF at 15-30°.

Hydrogenolytically removable protecting groups (for example CBZ orbenzyl) can be cleaved off, for example, by treatment with hydrogen inthe presence of a catalyst (for example a noble-metal catalyst, such aspalladium, advantageously on a support, such as carbon). Suitablesolvents here are those indicated above, in particular, for example,alcohols, such as methanol or ethanol, or amides, such as DMF. Thehydrogenolysis is generally carried out at temperatures between about 0and 100° and pressures between about 1 and 200 bar, preferably at 20-30°and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, forexample, on 5 to 10% Pd/C in methanol or using ammonium formate (insteadof hydrogen) on Pd/C in methanol/DMF at 20-30°.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline-earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalene-sulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline-earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxymethyl)-methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline-earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Isotopes

There is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I, aprodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otheriso-topes of other atoms is intended to be part of the presentinvention. An isotope-labelled compound of the formula I can be used ina number of beneficial ways. For example, an isotope-labelled compoundof the formula I into which, for example, a radioisotope, such as ³H or¹⁴C, has been incorporated is suitable for medicament and/or substratetissue distribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodiment of thepresent invention. An isotope-labelled compound of the formula I canusually be prepared by carrying out the procedures disclosed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus cause a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Thus, for example, in the case of oral administration in the form of atablet or capsule, the active-ingredient component can be combined withan oral, non-toxic and pharmaceutically acceptable inert excipient, suchas, for example, ethanol, glycerol, water and the like. Powders areprepared by comminuting the compound to a suitable fine size and mixingit with a pharmaceutical excipient comminuted in a similar manner, suchas, for example, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form, can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, can likewise be added in order to improve theavailability of the medicament after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinylpyrrolidone, adissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape, whichare broken up to form granules. The granules can be lubricated byaddition of stearic acid, a stearate salt, talc or mineral oil in orderto prevent sticking to the tablet casting moulds. The lubricated mixtureis then pressed to give tablets. The compounds according to theinvention can also be combined with a free-flowing inert excipient andthen pressed directly to give tablets without carrying out thegranulation or dry-pressing steps. A transparent or opaque protectivelayer consisting of a shellac sealing layer, a layer of sugar or polymermaterial and a gloss layer of wax may be present. Dyes can be added tothese coatings in order to be able to differentiate between differentdosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compound. Syrups can be prepared bydissolving the compound in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be formulated by dispersion of the compound in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

The compounds of the formula I and the pharmaceutically usable salts,tautomers and stereoisomers thereof can also be administered in the formof liposome delivery systems, such as, for example, small unilamellarvesicles, large unilamellar vesicles and multilamellar vesicles.Liposomes can be formed from various phospholipids, such as, forexample, cholesterol, stearylamine or phosphatidylcholines.

The compounds of the formula I and the pharmaceutically usable salts,tautomers and stereoisomers thereof can also be delivered usingmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds can also be coupled to solublepolymers as targeted medicament carriers. Such polymers may encompasspolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidophenol, polyhydroxyethylaspartamidophenolor polyethylene oxide polylysine, substituted by palmitoyl radicals. Thecompounds may furthermore be coupled to a class of biodegradablepolymers which are suitable for achieving controlled release of amedicament, for example polylactic acid, poly-epsilon-caprolactone,polyhydroxybutyric acid, polyorthoesters, polyacetals,polydihydroxypyrans, polycyanoacrylates and crosslinked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsuspended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multidose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilised) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition that requires treatment, andits severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or the pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios, and at least one further medicament active ingredient.

The invention also relates to a set (kit) consisting of separate packsof

-   (a) an effective amount of a compound of the formula I and/or the    pharmaceutically usable salts, tautomers and stereoisomers thereof,    including mixtures thereof in all ratios,-   and-   (b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound of theformula I and/or the pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

Use

The invention relates to the compounds of formula I for the use for thetreatment of cancer, septic shock, Primary open Angle Glaucoma (POAG),hyperplasia, rheumatoid arthritis, psoriasis, artherosclerosis,retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/orneurodegenerative diseases such as Alzheimers disease.

The invention relates to the use of compounds of formula I for thepreparation of a medicament for the treatment of cancer, septic shock,Primary open Angle Glaucoma (POAG), hyperplasia, rheumatoid arthritis,psoriasis, artherosclerosis, retinopathy, osteoarthritis, endometriosis,chronic inflammation, and/or neurodegenerative diseases such asAlzheimers disease.

The invention relates to a method of treating a mammal having a diseaseselected from cancer, septic shock, Primary open Angle Glaucoma (POAG),hyperplasia, rheumatoid arthritis, psoriasis, artherosclerosis,retinopathy, osteoarthritis, endometriosis, chronic inflammation, and/orneurodegenerative diseases such as Alzheimers disease, wherein themethod comprises administering to a mammal a therapeutically effectiveamount of a compound of formula I.

The present compounds are suitable as pharmaceutical active ingredientsfor mammals, especially for humans, in the treatment and control ofcancer diseases and inflammatory diseases.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be determined by in vitro tests.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow active agents such as anti IgM to induce a cellularresponse such as expression of a surface marker, usually between aboutone hour and one week. In vitro testing can be carried out usingcultivated cells from blood or from a biopsy sample. The amount ofsurface marker expressed are assessed by flow cytometry using specificantibodies recognising the marker.

The dose varies depending on the specific compound used, the specificdisease, the patient status, etc. A therapeutic dose is typicallysufficient considerably to reduce the undesired cell population in thetarget tissue while the viability of the patient is maintained. Thetreatment is generally continued until a considerable reduction hasoccurred, for example an at least about 50% reduction in the cellburden, and may be continued until essentially no more undesired cellsare detected in the body.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93)and models of transgenic animals (for example White et al., Oncogene,2001, 20, 7064-7072). For the determination of certain stages in thesignal transduction cascade, interacting compounds can be utilised inorder to modulate the signal (for example Stephens et al., BiochemicalJ., 2000, 351, 95-105). The compounds according to the invention canalso be used as reagents for testing kinase-dependent signaltransduction pathways in animals and/or cell culture models or in theclinical diseases mentioned in this application.

Measurement of the kinase activity is a technique which is well known tothe person skilled in the art. Generic test systems for thedetermination of the kinase activity using substrates, for examplehistone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages333-338) or the basic myelin protein, are described in the literature(for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol.Chem. 267, page 14535).

For the identification of kinase inhibitors, various assay systems areavailable. In scintillation proximity assay (Sorg et al., J. of.Biomolecular Screening, 2002, 7, 11-19) and flashplate assay, theradioactive phosphorylation of a protein or peptide as substrate withγATP is measured. In the presence of an inhibitory compound, a decreasedradioactive signal, or none at all, is detectable. Furthermore,homogeneous time-resolved fluorescence resonance energy transfer(HTR-FRET) and fluorescence polarisation (FP) technologies are suitableas assay methods (Sills et al., J. of Biomolecular Screening, 2002,191-214).

Other non-radioactive ELISA assay methods use specificphospho-antibodies (phospho-ABs). The phospho-AB binds only thephosphorylated substrate. This binding can be detected bychemiluminescence using a second peroxidase-conjugated anti-sheepantibody (Ross et al., 2002, Biochem. J.).

The present invention encompasses the use of the compounds of theformula I and/or physiologically acceptable salts, tautomers andsolvates thereof for the preparation of a medicament for the treatmentor prevention of cancer. Preferred carcinomas for the treatmentoriginate from the group cerebral carcinoma, urogenital tract carcinoma,carcinoma of the lymphatic system, stomach carcinoma, laryngealcarcinoma and lung carcinoma bowel cancer. A further group of preferredforms of cancer are monocytic leukaemia, lung adenocarcinoma, small-celllung carcinomas, pancreatic cancer, glioblastomas and breast carcinoma.

Also encompassed is the use of the compounds of the formula I and/orphysiologically acceptable salts, tautomers and solvates thereof for thepreparation of a medicament for the treatment and/or control of atumour-induced disease in a mammal, in which to this method atherapeutically effective amount of a compound according to theinvention is administered to a sick mammal in need of such treatment.The therapeutic amount varies according to the particular disease andcan be determined by the person skilled in the art without undue effort.

Particular preference is given to the use for the treatment of adisease, where the cancer disease is a solid tumour.

The solid tumour is preferably selected from the group of tumours of thesquamous epithelium, the bladder, the stomach, the kidneys, of head andneck, the oesophagus, the cervix, the thyroid, the intestine, the liver,the brain, the prostate, the urogenital tract, the lymphatic system, thestomach, the larynx and/or the lung.

The solid tumour is furthermore preferably selected from the group lungadenocarcinoma, small-cell lung carcinomas, pancreatic cancer,glioblastomas, colon carcinoma and breast carcinoma.

Preference is furthermore given to the use for the treatment of a tumourof the blood and immune system, preferably for the treatment of a tumourselected from the group of acute myeloid leukaemia, chronic myeloidleukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

The invention furthermore relates to the use of the compounds accordingto the invention for the treatment of bone pathologies, where the bonepathology originates from the group osteosarcoma, osteoarthritis andrickets.

The compounds of the formula I may also be administered at the same timeas other well-known therapeutic agents that are selected for theirparticular usefulness against the condition that is being treated.

The present compounds are also suitable for combination with knownanti-cancer agents. These known anti-cancer agents include thefollowing: oestrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic agents, antiproliferativeagents, prenyl-protein transferase inhibitors, HMG-CoA reductaseinhibitors, HIV protease inhibitors, reverse transcriptase inhibitorsand further angiogenesis inhibitors. The present compounds areparticularly suitable for administration at the same time asradiotherapy.

“Oestrogen receptor modulators” refers to compounds which interfere withor inhibit the binding of oestrogen to the receptor, regardless ofmechanism. Examples of oestrogen receptor modulators include, but arenot limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY 117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]phenyl2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646.

“Androgen receptor modulators” refers to compounds which interfere withor inhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole and abiraterone acetate.

“Retinoid receptor modulators” refers to compounds which interfere withor inhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid,α-difluoromethylornithine, ILX23-7553,trans-N-(4′-hydroxyphenyl)retinamide and N-4-carboxyphenylretinamide.

“Cytotoxic agents” refers to compounds which result in cell deathprimarily through direct action on the cellular function or inhibit orinterfere with cell myosis, including alkylating agents, tumour necrosisfactors, intercalators, microtubulin inhibitors and topoisomeraseinhibitors.

Examples of cytotoxic agents include, but are not limited to,tirapazimine, sertenef, cachectin, ifosfamide, tasonermin, lonidamine,carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine,fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin,estramustine, improsulfan tosylate, trofosfamide, nimustine,dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin,cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methylpyridine)platinum, benzylguanine,glufosfamide, GPX100,(trans,trans,trans)bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarisidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulfonyldaunorubicin (see WO00/50032).

Examples of microtubulin inhibitors include paclitaxel, vindesinesulfate, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine, docetaxol,rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,RPR109881, BMS184476, vinflunine, cryptophycin,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzenesulfonamide,anhydrovinblastine,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide,TDX258 and BMS188797.

Topoisomerase inhibitors are, for example, topotecan, hycaptamine,irinotecan, rubitecan,6-ethoxypropionyl-3′,4′-O-exobenzylidenechartreusin,9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H)propanamine,1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3′,4′:b,7]indolizino[1,2b]quinoline-10,13(9H,15H)-dione,lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350,BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane,2′-dimethylamino-2′-deoxyetoposide, GL331,N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(di-methylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-5,5a,6,8,8a,9-hexohydrofuro(3′,4′:6,7)naphtho(2,3-d)-1,3-dioxol-6-one,2,3-(methylene-dioxy)-5-methyl-7-hydroxy-8-methoxybenzo[c]phenanthridinium,6,9-bis[(2-amino-ethyl)amino]benzo[g]isoquinoline-5,10-dione,5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one,N-[1-[2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide,6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-oneand dimesna.

“Antiproliferative agents” include antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001 andantimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine,N-[5-(2,3-dihydrobenzofuryl)sulfonyl]-N′-(3,4-dichlorophenyl)urea,N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-mannohepto-pyranosyl]adenine,aplidine, ecteinascidin, troxacitabine,4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b]-1,4-thiazin-6-yl-(S)-ethyl]-2,5-thienoyl-L-glutamicacid, aminopterin, 5-fluorouracil, alanosine,11-acetyl-8-(carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1,11-diazatetracyclo(7.4.1.0.0)tetradeca-2,4,6-trien-9-ylaceticacid ester, swainsonine, lometrexol, dexrazoxane, methioninase,2′-cyano-2′-deoxy-N4-palmitoyl-1-B-D-arabinofuranosyl cytosine and3-aminopyridine-2-carboxaldehyde thiosemicarbazone. “Antiproliferativeagents” also include monoclonal antibodies to growth factors other thanthose listed under “angiogenesis inhibitors”, such as trastuzumab, andtumour suppressor genes, such as p53, which can be delivered viarecombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134,for example).

Test for the Inhibition of IKKε

IKKε—Kinase Assay (IKKepsilon)

Summary

The kinase assay is performed either as 384-well Flashplate assay (fore.g. Topcount measurement). 1 nM IKKε, 800 nM biotinylated IκBα(19-42)peptide (Biotin-C6-C6-GLKKERLLDDRHDSGLDSMKDEE) SEQ ID NO: 1 and 10 μMATP (spiked with 0.3 μCi ³³P-ATP/well) are incubated in a total volumeof 50 μl (10 mM MOPS, 10 mM Mg-acetat, 0.1 mM EGTA, 1 mMDithiothreitol,0.02% Brij35, 0.1% BSA, 0.1% BioStab, pH 7.5) with orwithout test compound for 2 hours at 30° C. The reaction is stopped with25 μl 200 mM EDTA. After 30 Min at room temperature the liquid isremoved and each well washed thrice with 100 μl 0.9% sodium chloridesolution. Non-specific reaction is determined in presence of 3 μMMSC2119074 (BX-795). Radioactivity is measured with Topcount(PerkinElmer). Results (e.g. IC₅₀-values) are calculated with programtools provided by the IT-department (e.g. AssayExplorer, Symyx).

Test for the Inhibition of TBK1

Enzyme Test

Summary

The kinase assay is performed as 384-well Flashplate assay assay (fore.g. Topcount measurement. 0.6 nM TANK binding kinase (TBK1), 800 nMbiotinylated MELK-derived peptide (Biotin-Ah-Ah-AKPKGNKDYHLQTCCGSLAYRRR)SEQ ID NO: 2 and 10 μM ATP (spiked with 0.25 μCi ³³P-ATP/well) areincubated in a total volume of 50 μl (10 mM MOPS, 10 mM Mg-acetat, 0.1mM EGTA, 1 mM DTT, 0.02% Brij35, 0.1% BSA, pH 7.5) with or without testcompound for 120 Min at 30° C. The reaction is stopped with 25 μl 200 mMEDTA. After 30 Min at room temperature the liquid is removed and eachwell washed thrice with 100 μl 0.9% sodium chloride solution.Nonspecific reaction is determined in presence of 100 nM Staurosporine.Radioactivity is measured in a Topcount (PerkinElmer). Results (e.g.IC₅₀-values) are calculated with program tools provided by theIT-department (e.g. AssayExplorer, Symyx).

Cell Test

Dose Response Inhibition of Phospho-IRF3 @ Ser 386cell/MDAMB468/INH/PHOS/IMAG/pIRF3

1. Scope

Although TBK1 and IKKε are best known as key players in the innateimmune response, recent findings have pointed towards a role for TBK1and IKKε in Ras-induced oncogenic transformation. TBK1 was identified asa RalB effector in the Ras-like (Ral)-guanine nucleotide exchange factor(GEF) pathway that is required for Ras-induced transformation. TBK1directly activates IRF3 which, upon phosphorylation, homodimerizes andtranslocates to the nucleus where it activates processes involved withinflammation, immune regulation, cell survival and proliferation.

This assay has been devised in order to assess the efficacy/potency ofTBK1/IKKε inhibitor compounds based on the immunocytochemical detectionof nuclear localised phospho-IRF3, a target directly downstream of TBK1.

Treatment with Polyinosine-polycytidylic acid (poly(I:C), a syntheticanalog of doublestranded RNA (dsRNA), a molecular pattern associatedwith viral infection which is recognized by Toll-like receptor 3 (TLR3)is used to induce TBK1/IKKe activity and IRF3 phosphorylation at Ser386.

2. Assay Overview

-   Day 1: MDA-MB-468 cells are detached with HyQ-Tase, counted, and    seeded into a 384-well clear bottom TC-surface plate at density of    10,000 cells per well in a total volume of 35 ul complete medium.    Alternatively cells are directly seeded from frozen vials.-   Day 2: Cells are pre-treated with inhibitor compounds for 1 h prior    to Poly(I:C) stimulation. After 2 h of incubation with Poly(I:C),    cells are fixed in (para)formaldehyde (PFA) and permeabilized with    methanol (MeOH). The cells are then blocked and incubated with an    anti-pIRF3 antibody at 4oC overnight.-   Day 3: The primary antibody is washed off, an    AlexaFluor488-conjugated secondary is added, cells are    counterstained with propidium iodide followed by image acquisition    on IMX Ultra high content reader.

3. Reagents, Materials

-   -   cells: ATCC HTB 132, Burger lab (MP-CB 2010-327 or        MDA-MB-468/10)    -   plating medium=culture medium:        -   RPMI 1640, Invitrogen # 31870        -   10% FCS, Invitrogen # 10270-106            -   2 mM Glutamax, Invitrogen #35050-038        -   1 mM Natrium-Pyruvat, Invitrogen # 11360            -   1% Pen/Strep        -   37° C., 5% CO2    -   plates: black/clear bottom 384well bottom cell culture plates,        Falcon #35 3962 or Greiner #781090    -   subcultivation: HyQ-Tase, Thermo Scientific (HyClone) #        SV30030.01    -   other reagents:    -   Poly(I:C) (LMW), Invivogen # tlrl-picw (prepare 20 mg/ml stock        in sterile PBS, denature 30 min 55oC in waterbath, slowly cool        to RT, store at −20 oC in aliquots)    -   reference inhibitor: MSC2119074A-4=BX-795 (IC50: 200-800 nM)        -   inhibitory control: 10 μM MSC2119074A-4=BX-795        -   neutral control: 0.5% DMSO    -   a 10point dose-response curve with MSC2119074A-4=BX-795 is        included in each experiment    -   Hepes, Merck #1.10110    -   PBS 1×DPBS, Invitrogen # 14190    -   Formaldehyde (methanol-free, 16%, ultrapure EM Grade),        Polysciences # 18814 (storage RT), final conc.: 4%    -   Methanol, Merck # 1.06009.1011 (−20 oC pre-cooled)    -   Goat Serum, PAA # B15-035 (storage 4 oC, long time −20 oC),        final conc.: 10%    -   BSA (IgG and Protease free, 30%), US-Biological # A1317(storage        4 oC, long time −20 oC), final conc.: 2%    -   Tween 20 Detergent, Calbiochem # 655204 (storage RT), (prepare        10% stock in water; final conc.: 0.1%)    -   anti-pIRF-3 Rabbit mAb, Epitomics # 2526-B (storage −20 oC),        final conc.: 1:2000 in PBS/2% BSA    -   Alexa Fluor Goat-anti-Rabbit-488, Invitrogen # A11034 or #        A11008 (storage 4 oC, dark), final conc.: 1:2000 in PBS/2%        BSA/0.1% Tween    -   Propidium Iodide (PI), Fluka # 81845, 1 mg/ml in H2O (storage 4        oC, dark), final conc.: 0.2 μg/ml

4. Procedure

HPLC/MS conditions:

-   column: Chromolith Speed ROD RP-18e, 50×4.6 mm²-   gradient: A:B=96:4 to 0:100-   flow rate: 2.4 ml/min-   eluent A: water+0.05% formic acid-   eluent B: acetonitrile+0.04% formic acid-   wavelength: 220 nm-   mass spectroscopy: positive mode

¹H NMR: coupling constant J [Hz].

Preferred general scheme for manufacturing compounds of formula I

Experimental Procedure:

To a stirred solution of 5-bromo-2-amino-nicotinic acid (500 mg, 2.3mol, 1 eq) and 4-aminopyridine (260 mg, 2.7 mol, 1.2 eq) in dry DMF (5ml) is added HATU (1.31 g, 3.4 mol, 1.5 eq) and N-methylmorpholine (690mg, 6.9 mol, 3 eq) and allowed to stir for 3 h. After the completion ofthe reaction, the reaction mixture is concentrated; water is added,solid precipitated out and filtered, washed with NaHCO₃ and water toafford the product.

¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.47-8.46 (d, J=5.4 Hz, 2H),8.25-8.22 (dd, J=2.4, 7.4 Hz, 2H), 7.69-7.67 (d, J=6.2 Hz, 2H).

To a stirred solution of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide (1eq) in toluene: ethanol (4:1), substituted boronic acid (1.2 eq), 2 MNa₂CO₃ (1.5 eq) is added and degassed for 15 min under N₂ atmosphere. Tothis reaction mixture Pd(PPh₃)₄ (0.012 eq) is added and heated to 100°C. for 18 hr. After the completion of the reaction the mixture is passedthrough a Celite bed to remove the inorganic impurities. The filtrate isconcentrated under vacuum. Column chromatography affords the purecompound.

EXAMPLE 1

The preparation of2-Amino-5-(5-piperidin-1-ylmethyl-thiophen-2-yl)-N-pyridin-4-yl-nicotinamide(“A1”) is carried out analogously to the following scheme

1.1 2-Amino-5-bromo-N-pyridin-4-yl-nicotinamide:

2.0 g of 2-amino-5-bromonicotinic acid and 1.06 g of 4-amino-pyridineare dissolved in 20 mL DMF. 5.26 g HATU((2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate) and 3.04 mL N-methylmorpholine are added to thesolution.

The mixture is stirred for 5 h at room temperature. The DMF isevaporated and the residue is triturated with water. The solid isfiltered off and washed with NaHCO₃ solution and water. 2.5 g of a lightbrown solid is obtained;

HPLC/MS: 1.13 min, [M+H]=293;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.51 (s, 1H, NH), 8.48 (d, J=6.0,2H), 8.25 (dd, J=10.8, 2.3, 2H), 7.69 (d, J=6.3, 2H), 7.18 (s, 2H, NH₂).

1.22-Amino-5-(5-piperidin-1-ylmethyl-thiophen-2-yl)-N-pyridin-4-yl-nicotinamide(“A1”)

200 mg of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide and 218 mg5-(1-piperidinylmethyl)-thiophene-2-boronic acid pinacol ester aredissolved in 8 ml of DMF. 0.84 ml of a 2 molar Na₂CO₃ solution is addedunder nitrogen. 7.81 mg of tetrakis(triphenylphosphin)-palladium(0) isadded. The mixture is stirred for 6 h at 100° C.

The reaction mixture is cooled to room temperature and the DMF isevaporated. Water is added and the resulting precipitate is filteredoff, washed with water and dried. The solid is triturated with ethylacetate and filtered off. 47 mg of the desired product “A1” are obtainedas light brown solid;

HPLC/MS: 1.08 min, [M+H]=394;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.58 (s, 1H, NH), 8.48 (d, J=6.2,2H), 8.44 (d, J=2.3, 1H), 8.22 (d, J=2.3, 1H), 7.71 (dd, J=4.8, 1.5,2H), 7.25 (d, J=3.5, 1H), 7.13 (s, 2H, NH₂), 6.93 (d, J=3.5, 1H), 3.61(s, 2H), 2.37 (br, 4H), 1.51 (m, 4H), 1.39 (m, 2H).

The following compounds are obtained analogously

2-Amino-N-pyridin-4-yl-5-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-nicotinamide(“A2”)

The reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with5-(1-pyrrolidinyl-methyl)thiophene-2-boronic acid pinacol ester givescompound “A2”;

HPLC/MS: 1.16 min, [M+H]=380;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.51 (s, 1H, NH), 8.51-8.46 (m, 3H),8.27 (d, J=2.4, 1H), 8.24 (d, J=2.4, 1H), 7.69 (m, 3H), 7.18 (s, 2H),4.70 (s, 2H), 3.54 (m, 2H), 3.23 (m, 2H), 2.12 (m, 2H), 1.98 (m, 2H);

2-Amino-5-(5-methyl-thiophen-2-yl)-N-pyridin-4-yl-nicotinamide (“A3”)

The reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with5-methylthiophene-2-boronic acid pinacol ester gives the compound “A3”;

HPLC/MS: 1.45 min, [M+H]=311;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.74 (s, 1H, NH), 8.53 (d, J=4.9,2H), 8.40 (d, J=2.3, 1H), 8.22 (d, J=2.1, 1H), 7.79 (d, J=11.8, 2H),7.22 (d, J=3.5, 1H), 7.12 (s, 2H, NH₂), 6.86-6.74 (m, 1H), 2.47 (s, 3H);

2-Amino-5-(3-pyrazol-1-yl-phenyl)-N-pyridin-4-yl-nicotinamide (“A4”)

The reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazolegives the compound “A4”;

HPLC/MS: 1.44 min, [M+H]=357;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.40 (s, 1H, NH), 8.74 (t, J=7.2,2H), 8.72 (s, 1H), 8.62 (d, J=2.3, 1H), 8.53 (d, J=2.4, 1H), 8.19 (d,J=7.2, 2H), 8.16 (t, J=1.8, 1H), 7.83 (ddd, J=7.9, 2.1, 1.0, 1H), 7.78(d, J=1.6, 1H), 7.67 (dd, J=6.6, 1.4, 1H), 7.60 (t, J=7.9, 1H), 7.38 (s,2H), 6.58 (dd, J=2.4, 1.8, 1H);

2-Amino-5-(4-pyrazol-1-yl-phenyl)-N-pyridin-4-yl-nicotinamide (“A5”)

The reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with[4-(1H-pyrazol-1-yl)phenyl]boronic acid gives the compound “A5”;

HPLC/MS: 1.38 min, [M+H]=357;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.60 (s, 1H, NH), 8.59 (d, J=2.4,1H), 8.54 (d, J=2.4, 1H), 8.52-8.45 (m, 2H), 8.40 (d, J=2.4, 1H),7.98-7.92 (m, 2H), 7.88-7.84 (m, 2H), 7.78-7.72 (m, 3H), 7.16 (d,J=15.2, 2H), 6.60-6.56 (m, 1H);

2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamide(“A6”)

The reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolegives the compound “A6”;

HPLC/MS: 1.05 min, [M+H]=339;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.37 (s, 1H, NH), 8.75 (d, J=7.2,2H), 8.51 (d, J=2.2, 1H), 8.34 (d, J=2.3, 1H), 8.18 (d, J=7.2, 2H), 8.12(s, 1H), 7.89 (s, 1H), 4.29 (t, J=5.3, 3H), 3.72 (t, J=5.3, 3H), 3.23(s, 3H);

2-Amino-N-pyridin-4-yl-5-(4-sulfamoyl-phenyl)-nicotinamide (“A7”)

The reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide withbenzene-sulfonamide-4-boronic acid pinacol ester gives the compound“A7”;

HPLC/MS: 1.12 min, [M+H]=370;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.57 (s, 1H, NH), 8.61 (d, J=2.3,1H), 8.55-8.46 (m, 2H), 8.42 (d, J=2.4, 1H), 7.92 (m, 4H), 7.80-7.65 (m,2H), 7.35 (s, 2H), 7.24 (s, 2H);

2-Amino-N-(2-methyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A8”)

The reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamidewith 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester givesthe compound “A8”;

HPLC/MS: 1.02 min, [M+H]=410;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.49 (s, 1H, NH), 8.44 (d, J=2.3,1H), 8.35 (d, J=5.6, 1H), 8.23 (d, J=2.4, 1H), 7.59 (d, J=1.7, 1H), 7.53(dd, J=5.6, 1.9, 1H), 7.32-7.27 (d, J=3.5, 1H), 7.12 (s, 2H), 6.96 (d,J=3.5, 1H), 3.71 (s, 2H), 3.61-3.53 (m, 4H), 2.45 (s, 3H), 2.43 (m, 4H);

2-Amino-N-(2-ethoxy-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A9”)

The reaction of 2-amino-5-bromo-N-(2-ethoxy-pyridin-4-yl)-nicotinamidewith 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester givesthe compound “A9”;

HPLC/MS: 1.37 min, [M+H]=440;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.51 (s, 1H, NH), 8.44 (d, J=2.3,1H), 8.19 (d, J=2.3, 1H), 8.06 (d, J=5.7, 1H), 7.26 (m, 2H), 7.22 (d,J=1.6, 1H), 7.12 (s, 2H), 6.96 (d, J=3.5, 1H), 4.30 (q, J=7.0, 2H), 3.66(s, 2H), 3.58 (m, 4H), 2.42 (br, 4H), 1.31 (t, J=7.0, 3H);

EXAMPLE 23-Amino-6-(5-morpholin-4-ylmethyl-thiophen-2-yl)-pyrazine-2-carboxylicacid pyridin-4-ylamide (“A10”)

2.1 3-Amino-6-bromo-pyrazine-2-carboxylic acid pyridin-4-ylamide

The title compound is obtained from3-amino-6-bromo-pyrazine-2-carboxylic acid and 4-aminopyridine using thesame method as described in step 1 for “A1”;

HPLC/MS: 1.18 min, [M+H]=294.

2.23-Amino-6-(5-morpholin-4-ylmethyl-thiophen-2-yl)-pyrazine-2-carboxylicacid pyridin-4-ylamide (“A10”)

The title compound is prepared analogously to step 2 for “A1”; HPLC/MS:1.08 min, [M+H]=397.

EXAMPLE 3 6-Amino-6′-piperazin-1-yl-[3,3′]bipyridinyl-5-carboxylic acidpyridin-4-ylamide (“A11”)

3.14-[6′-Amino-5′-(pyridin-4-ylcarbamoyl)-[3,3′]bipyridinyl-6-yl]-piperazine-1-carboxylicacid tert-butyl ester

The title compound is obtained from2-amino-5-bromo-N-(2-ethoxy-pyridin-4-yl)-nicotinamide and2-(4-tert-butoxycarbonylpiperazin-1-yl)pyridine-5-boronic acid, pinacolester analogously to step 2 for “A1”; HPLC/MS: 1.43 min, [M+H]=476.

3.2 1.1 g of4-[6′-amino-5′-(pyridin-4-ylcarbamoyl)-[3,3′]bipyridinyl-6-yl]-piperazine-1-carboxylicacid tert-butyl ester are dissolved in 25 ml dioxane. 11 ml of HCl indioxane (4 molar) is added. The mixture is stirred 3 h at roomtemperature. The mixture is filtered and the solid washed with dioxane.The product is purified by chromatography; HPLC/MS: 1.02 min, [M+H]=376;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 9.08 (d, J=2.2, 1H), 8.84 (d, J=7.3,2H), 8.77 (d, J=2.1, 1H), 8.67 (d, J=2.3, 1H), 8.48 (dd, J=9.5, 2.4,1H), 8.38 (d, J=7.3, 2H), 7.54 (d, J=9.5, 1H), 4.09-3.96 (m, 4H),3.47-3.35 (m, 4H).

EXAMPLE 4

The following compounds are obtained analogously to example 2

3-Amino-6-(1-[1,3]dioxolan-2-ylmethyl-1H-pyrazol-4-yl)-pyrazine-2-carboxylicacid pyridin-4-ylamide (“A12”)

The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acidpyridin-4-ylamide (synthesis described for “A10”) with1-[1,3]dioxolan-2-ylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolegives the compound “A12”

HPLC/MS: 1.02 min, [M+H]=376;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.55 (s, 1H, NH), 8.71 (s, 1H),8.55-8.41 (m, 3H), 8.27 (s, 1H), 7.91-7.86 (m, 2H), 7.51 (s, 2H), 5.22(t, J=4.3, 1H), 4.30 (d, J=4.3, 2H), 3.96-3.70 (m, 4H);

3-Amino-6-(5-piperidin-1-ylmethyl-thiophen-2-yl)-pyrazine-2-carboxylicacid pyridin-4-ylamide (“A13”)

The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acidpyridin-4-ylamide (synthesis described for “A10”) with1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-piperidinegives the compound “A13”;

HPLC/MS: 1.13 min, [M+H]=395;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.41 (s, 1H, NH), 8.80 (s, 1H), 8.51(dd, J=4.8, 1.6, 2H), 7.82 (dd, J=4.8, 1.6, 2H), 7.67 (d, J=3.6, 1H),7.63 (s, 2H), 6.98 (d, J=3.6, 1H), 3.64 (s, 2H), 2.40 (s, 4H), 1.59-1.32(m, 6H);

3-Amino-6-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-pyrazine-2-carboxylicacid pyridin-4-ylamide (“A14”)

The reaction of 3-amino-6-bromo-pyrazine-2-carboxylic acidpyridin-4-ylamide (synthesis described for “A10”) with1-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-pyrrolidinegives the compound “A14”;

HPLC/MS: 1.08 min, [M+H]=381;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.40 (s, 1H, NH), 8.83 (s, 1H), 8.51(dd, J=4.8, 1.5, 2H), 7.88-7.75 (m, 2H), 7.67 (d, J=3.6, 1H), 7.63 (s,2H), 6.96 (d, J=3.6, 1H), 3.78 (s, 2H), 2.51 (m, 4H), 1.78-1.62 (m, 4H);

2-Amino-N-(2-methyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-3-yl)-nicotinamide(“A15”)

Reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamide with4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-morpholinegives the compound “A15”;

HPLC/MS: 0.99 min, [M+H]=410;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.45 (s, 1H, NH), 8.53 (d, J=2.3,1H), 8.35 (d, J=5.6, 1H), 8.30 (d, J=2.3, 1H), 7.69 (d, J=1.4, 1H), 7.60(d, J=1.7, 1H), 7.56-7.50 (m, 1H), 7.44 (s, 1H), 7.04 (s, 2H), 3.71 (s,2H), 3.61-3.58 (m, 4H), 2.45 (m, 7H).

EXAMPLE 52-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-N-pyridazin-4-yl-nicotinamide(“A16”)

5.1 2-Amino-5-bromo-N-pyridazin-4-yl-nicotinamide

The title compound is obtained from 2-amino-5-bromonicotinic acid and4-aminopyridazine analogously to “A1” in step 1;

HPLC/MS: 1.40 min, [M+H]=294.

5.22-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-N-pyridazin-4-yl-nicotinamideis obtained from 2-amino-5-bromo-N-pyridazin-4-yl-nicotinamide and5-(4-morpholinylmethyl)thiophen-2-boronic acid pinacol ester analogouslyto “A1” in step 2; HPLC/MS: 1.15 min, [M+H]=397;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.78 (s, 1H, NH), 9.47 (d, J=1.9,1H), 9.08 (d, J=5.9, 1H), 8.48 (d, J=2.3, 1H), 8.27 (d, J=2.3, 1H), 8.03(dd, J=5.9, 2.7, 1H), 7.27 (d, J=3.1, 1H), 7.20 (s, 2H), 6.98 (s, 1H),3.68 (s, 2H), 3.59 (s, 4H), 2.48-2.35 (m, 4H).

The following compounds are obtained analogously

2-Amino-5-(1-benzyl-1H-pyrazol-4-yl)-N-(2-methyl-pyridin-4-yl)-nicotinamide(“A17”)

Reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamide with4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophen-2-ylmethyl]-morpholinegives the compound “A17”);

HPLC/MS: 1.41 min, [M+H]=385;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.45 (s, 1H, NH), 8.53 (d, J=2.3,1H), 8.35 (d, J=5.6, 1H), 8.30 (d, J=2.3, 1H), 7.69 (d, J=1.4, 1H), 7.60(d, J=1.7, 1H), 7.55 (dd, J=5.6, 1.9, 1H), 7.44 (s, 1H), 7.04 (s, 2H),3.71 (s, 2H), 3.63-3.57 (m, 4H), 2.45 (s+m, 7H);

2-Amino-5-(3-pyrazol-1-yl-phenyl)-N-pyridazin-4-yl-nicotinamide (“A18”)

Reaction of 2-amino-5-bromo-N-pyridazin-4-yl-nicotinamide (see step 1 inthe synthesis of “A16”) and1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-pyrazolegives the compound “A18”;

HPLC/MS: 1.15 min, [M+H]=397;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.06 (s, 1H, NH), 9.54 (d, J=2.1,1H), 9.14 (d, J=5.9, 1H), 8.67 (dd, J=4.1, 2.4, 2H), 8.58 (d, J=2.3,1H), 8.19 (t, J=1.8, 1H), 8.14 (dd, J=6.0, 2.7, 1H), 7.89-7.80 (m, 1H),7.77 (d, J=1.7, 1H), 7.68 (d, J=7.9, 1H), 7.59 (t, J=7.9, 1H), 7.37 (s,2H), 6.60-6.56 (m, 1H);

2-Amino-N-(3-methyl-pyridin-4-yl)-5-(4-pyrazol-1-yl-phenyl)-nicotinamide(“A19”)

Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with[4-(1H-pyrazol-1-yl)phenyl]boronic acid gives the compound “A19”;

HPLC/MS: 1.41 min, [M+H]=371;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.07 (s, 1H, NH), 8.59 (d, J=2.3,1H), 8.55 (d, J=2.4, 1H), 8.45 (s, 1H), 8.44 (d, J=2.3, 1H), 8.40 (d,J=5.3, 1H), 7.96-7.91 (m, 2H), 7.90-7.83 (m, 2H), 7.76 (d, J=1.6, 1H),7.53 (d, J=5.3, 1H), 7.17 (s, 2H), 6.60-6.54 (m, 1H), 2.28 (s, 3H);

2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-(2-methyl-pyridine-4-yl)-nicotinamide(“A20”)

Reaction of 2-amino-5-bromo-N-(2-methyl-pyridin-4-yl)-nicotinamide with1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolegives the compound “A20”;

HPLC/MS: 1.11 min, [M+H]=353;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.44 (s, 1H, NH), 8.43 (d, J=2.2,1H), 8.36 (d, J=5.6, 1H), 8.20 (d, J=2.2, 1H), 8.09 (s, 1H), 7.86 (d,J=0.5, 1H), 7.62 (s, 1H), 7.55 (d, J=5.6, 1H), 6.94 (s, 2H), 4.33-4.22(m, 2H), 3.76-3.66 (m, 2H), 3.25 (s, 3H), 2.46 (s, 3H);

2-Amino-N-(3-methyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A21”)

Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives thecompound “A21”; HPLC/MS: 0.97 min, [M+H]=410;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.8 (br, 1H, NH), 8.72 (d, J=2.2,1H), 8.70 (s, 1H), 8.67 (d, J=6.7, 1H), 8.52-8.47 (m, 2H), 7.54 (d,J=3.7, 1H), 7.34 (d, J=3.7, 1H), 4.61 (s, 2H), 4.01-3.87 (m, 2H), 3.67(m, 2H), 3.33 (m, 2H), 3.14 (m, 2H);

2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-(3-methyl-pyridin-4-yl)-nicotinamide(“A22”)

Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolegives the compound “A22”; HPLC/MS: 1.07 min, [M+H]=353;

2-Amino-5-(4′-methyl-biphenyl-3-yl)-N-pyridin-4-yl-nicotinamide (“A23”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with[3-(p-tolyl)phenyl]-boronic acid gives the compound “A23”;

HPLC/MS: 1.90 min, [M+H]=381;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 11.4 (s, 1H, NH), 9.03 (d, J=2.2, 1H),8.75 (d, J=6.6, 2H), 8.71 (d, J=2.1, 1H), 8.25 (d, J=7.3, 2H), 8.00 (s,1H), 7.69 (dd, J=10.1, 8.7, 2H), 7.62 (d, J=8.1, 2H), 7.56 (t, J=7.7,1H), 7.37 (br, 2H, NH2), 7.25 (d, J=8.1, 2H), 2.31 (s, 3H);

2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-pyridazin-4-yl-nicotinamide(“A24”)

Reaction of 2-amino-5-bromo-N-pyridazin-4-yl-nicotinamide (see step 1 inthe synthesis of “A16”) with1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolegives the compound “A24”;

HPLC/MS: 1.21 min, [M+H]=340;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.98 (br, 1H, NH), 9.51-9.48 (m, 1H),9.17 (d, J=6.1, 1H), 8.48 (d, J=2.2, 1H), 8.42 (d, J=1.6, 1H), 8.14 (m,2H), 7.91 (s, 1H), 7.36 (br, 2H), 4.29 (t, J=5.3, 2H), 3.72 (t, J=5.3,3H), 3.25 (s, 3H);

2-Amino-5-(1-carbamoylmethyl-1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide(“A25”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetamidegives the compound “A25”; HPLC/MS: 0.94 min, [M+H]=338;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.51 (s, 1H, NH), 8.48 (dd, J=4.8,1.5, 2H), 8.44 (d, J=2.3, 1H), 8.22 (d, J=2.3, 1H), 8.08 (d, J=0.5, 1H),7.88 (d, J=0.6, 1H), 7.72 (dd, J=4.8, 1.6, 2H), 7.49 (s, 1H), 7.24 (s,1H), 6.94 (s, 2H), 4.78 (s, 2H);

2-Amino-N-(2,6-dimethyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A26”)

Reaction of 2-amino-5-bromo-N-(2,6-dimethyl-pyridin-4-yl)-nicotinamidewith 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester givesthe compound “A26”; HPLC/MS: 1.09 min, [M+H]=424;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.43 (s, 1H, NH), 8.43 (d, J=2.3,1H), 8.21 (d, J=2.3, 1H), 7.43 (s, 2H), 7.26 (d, J=3.5, 1H), 7.14 (s,2H), 6.96 (d, J=3.5, 1H), 3.68 (s, 2H), 3.64-3.54 (m, 4H), 2.53-2.47 (m,4H), 2.43 (s, 6H).

EXAMPLE 62-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-N-pyrimidin-4-yl-nicotinamide(“A27”)

6.1 Reaction of 2-amino-5-bromo-pyridine-3-carboxylic acid withpyrimidin-4-amine according to the synthesis described for “A1” step 1,gives 2-amino-5-bromo-N-pyrimidin-4-yl-pyridine-3-carboxamide.

6.2 “A27” is prepared from2-amino-5-bromo-N-pyrimidin-4-yl-pyridine-3-carboxamide and5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester accordingto step 2 of the synthesis of “A1”;

HPLC/MS: 1.27 min, [M+H]=397;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.34 (s, 1H, NH), 8.97 (d, J=0.9,1H), 8.72 (d, J=5.8, 1H), 8.46 (d, J=2.3, 1H), 8.40 (d, J=2.3, 1H), 8.14(dd, J=5.8, 1.2, 1H), 7.33 (d, J=3.5, 1H), 7.25 (s, 2H), 6.97 (d, J=3.4,1H), 3.69 (s, 2H), 3.65-3.56 (m, 4H), 2.45 (s, 4H).

EXAMPLE 72-Amino-N-furo[3,2-b]pyridin-7-yl-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-nicotinamide(“A28”)

7.1 Reaction of 2-amino-5-bromo-pyridine-3-carboxylic acid withfuro[3,2-b]pyridin-7-amine according to the synthesis described for “A1”step 1, gives2-Amino-5-bromo-N-furo[3,2-b]pyridin-7-yl-pyridine-3-carboxamide.

7.2 “A28” is obtained from2-amino-5-bromo-N-furo[3,2-b]pyridin-7-yl-pyridine-3-carboxamide and1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazoleaccording to the procedure described for “A1” step 2;

HPLC/MS: 1.22 min, [M+H]=379;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.70 (s, 1H, NH), 8.48-8.44 (m, 2H),8.34 (d, J=2.0, 1H), 8.32 (d, J=2.2, 1H), 8.10 (s, 1H), 7.88 (s, 1H),7.60 (d, J=5.3, 1H), 7.15 (d, J=2.2, 1H), 7.02 (s, 2H), 4.28 (t, J=5.3,2H), 3.71 (t, J=5.3, 2H), 3.25 (s, 3H).

The following compounds are obtained analogously

2-Amino-N-furo[3,2-b]pyridin-7-yl-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A29”)

Reaction of2-amino-5-bromo-N-furo[3,2-b]pyridin-7-yl-pyridine-3-carboxamide(synthesis described above) with5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives thecompound “A29”;

HPLC/MS: 1.17 min, [M+H]=436;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.85 (s, 1H, NH), 8.48 (t, J=3.5,2H), 8.36 (d, J=2.3, 1H), 8.33 (d, J=2.2, 1H), 7.62 (d, J=5.3, 1H), 7.30(d, J=3.5, 1H), 7.23 (s, 2H), 7.16 (d, J=2.2, 1H), 6.98 (d, J=3.5, 1H),3.68 (s, 2H), 3.62-3.56 (m, 4H), 2.44 (m, 4H);

4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid methylester (“A30”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-methoxycarbonyl)-benzoic acid gives the compound “A30”; HPLC/MS: 1.48min, [M+H]=349;

4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid (“A31”)

190 mg of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid methyl ester are dissolved in 20 ml of MeOH. 175 mg Na₂CO₃ in 6 mlof water are added.

The reaction mixture is stirred over night at 50° C.

The desired material “A31” is purified by chromatography;

HPLC/MS: 1.28 min, [M+H]=335;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 13.24-12.61 (m, 1H, OH), 11.36 (s, 1H,NH), 8.74 (d, J=6.7, 2H), 8.69 (d, J=2.4, 1H), 8.51 (d, J=2.4, 1H), 8.18(d, J=7.2, 2H), 8.06-7.98 (m, 2H), 7.90-7.81 (m, 2H), 7.40 (s, 2H);

3-{4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-phenyl}-propionicacid (“A32”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with3-(4-boronophenyl)-propanoic acid gives the compound “A32”; HPLC/MS:1.28 min, [M+H]=363;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 12.09 (s, 1H, OH), 10.52 (s, 1H, NH),8.48 (dd, J=6.7, 4.2, 3H), 8.31 (d, J=2.2, 1H), 7.72 (d, J=6.1, 2H),7.62 (d, J=8.1, 2H), 7.32 (d, J=8.1, 2H), 7.09 (s, 2H), 2.86 (t, J=7.5,2H), 2.56 (t, J=7.5, 2H);

2-Amino-N-(3-chloro-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A33”)

Reaction of 2-amino-5-bromo-N-(3-chloro-4-pyridyl)pyridine-3-carboxamidewith 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester givesthe compound “A33”; HPLC/MS: 1.25 min, [M+H]=343;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.30 (s, 1H, NH), 8.70 (s, 1H), 8.53(d, J=5.3, 1H), 8.49 (d, J=2.3, 1H), 8.30 (d, J=2.4, 1H), 7.79 (d,J=5.3, 1H), 7.28 (d, J=3.5, 1H), 7.21 (s, 2H), 6.97 (d, J=3.5, 1H), 3.68(s, 2H), 3.62-3.55 (m, 4H), 2.44 (s, 4H),

2-Amino-5-(1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide (“A34”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gives thecompound “A34”;

HPLC/MS: 0.89 min, [M+H]=281;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 12.89 (s, 1H, NH), 10.48 (s, 1H, NH),8.47 (dd, J=10.1, 4.2, 3H), 8.23 (d, J=2.2, 1H), 8.11 (s, 1H), 7.91 (s,1H), 7.71 (dd, J=10.9, 9.6, 2H), 6.91 (s, 2H);

4-{[2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-pyridine-3-carbonyl]-amino}-nicotinicacid methyl ester (“A35”)

Reaction of methyl4-[(2-amino-5-bromo-pyridine-3-carbonyl)amino]pyridine-3-carboxylatewith 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester givescompound “A35”; HPLC/MS: 1.36 min, [M+H]=454;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] (s, 1H, NH), 9.04 (s, 1H), 8.70 (d,J=5.8, 1H), 8.52 (d, J=2.3, 1H), 8.34 (d, J=5.8, 1H), 8.20 (d, J=2.3,1H), 7.31 (s, 2H), 7.26 (d, J=3.5, 1H), 6.98 (d, J=3.5, 1H), 3.92 (s,3H), 3.69 (s, 2H), 3.62-3.53 (m, 4H), 2.44 (s, 4H);

N-(2-Acetylamino-pyridin-4-yl)-2-amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A36”)

Reaction ofN-(2-acetamido-4-pyridyl)-2-amino-5-bromo-pyridine-3-carboxamide with5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives thecompound “A36”; HPLC/MS: 1.14 min, [M+H]=453;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.63 (s, 1H, NH), 10.37 (s, 1H, NH),8.43 (d, J=2.3, 1H), 8.38 (d, J=1.2, 1H), 8.23 (d, J=2.3, 1H), 8.20 (d,J=5.6, 1H), 7.60 (dd, J=5.6, 1.9, 1H), 7.26 (d, J=3.5, 1H), 7.13 (s,2H), 6.96 (d, J=3.5, 1H), 3.67 (s, 2H), 3.61-3.57 (m, 4H), 2.43 (s, 4H),2.09 (s, 3H);

3-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-2-yl]-benzoic acid (“A37”)

1. (3-Methoxycarbonylphenyl)boronic acid and2-amino-5-bromo-N-pyridin-4-yl-nicotinamide are reacted analogously to“A1” step 2 to give methyl3-[6-amino-5-(4-pyridylcarbamoyl)-3-pyridyl]benzoate.

2. “A37” is obtained from methyl3-[6-amino-5-(4-pyridylcarbamoyl)-3-pyridyl]benzoate using the methoddescribed for “A31”;

HPLC/MS: 1.19 min, [M+H]=335;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 13.07 (br, 1H, OH), 11.41 (s, 1H, NH),8.74 (d, J=7.2, 2H), 8.64 (d, J=2.4, 1H), 8.48 (d, J=2.4, 1H), 8.26 (t,J=1.6, 1H), 8.19 (d, J=7.2, 2H), 8.01-7.88 (m, 2H), 7.62 (t, J=7.8, 1H),7.38 (s, 2H);

2-Amino-N-(3-chloro-pyridin-4-yl)-5-[1-(2-methoxy-ethyl-)-1H-pyrazol-4-yl]nicotinamide(“A38”)

Reaction of 2-amino-5-bromo-N-(3-chloro-4-pyridyl)pyridine-3-carboxamidewith1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazolegives the compound “A38”; HPLC/MS: 1.39 min, [M+H]=373;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 10.16 (s, 1H, NH), 8.69 (s, 1H), 8.51(d, J=5.3, 1H), 8.46 (d, J=2.2, 1H), 8.28 (d, J=2.3, 1H), 8.09 (s, 1H),7.86 (s, 1H), 7.79 (d, J=5.3, 1H), 7.00 (s, 2H), 4.28 (t, J=5.3, 2H),3.71 (t, J=5.3, 2H), 3.24 (s, 4H);

2-Amino-N-(4-methoxy-phenyl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A39”)

Reaction of 2-amino-5-bromo-N-(4-methoxyphenyl)pyridine-3-carboxamidewith 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester givesthe compound “A39”; HPLC/MS: 1.46 min, [M+H]=425;

2-Amino-N-(6-methoxy-pyridin-3-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A40”)

Reaction of2-amino-5-bromo-N-(6-methoxy-3-pyridyl)pyridine-3-carboxamide with5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives thecompound “A40”; HPLC/MS: 1.29 min, [M+H]=426;

EXAMPLE 82-Amino-N-(3-methylcarbamoyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide(“A41”)

100 mg of methyl4-[[2-amino-5-[5-(morpholinomethyl)-2-thienyl]pyridine-3-carbonyl]amino]pyridine-3-carboxylate(MSC 2392368) are dissolved in 4 ml THF and 4 ml of methylamine (40% inwater) are added. The mixture is stirred for 2 h at room temperature.The mixture is evaporated and treated with petrol ether and ethylacetate. After filtration 79 mg of a yellow solid is obtained;

HPLC/MS: 1.17 min, [M+H]=453;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 12.76 (s, 1H), 9.05 (d, J=4.3, 1H),8.94 (s, 1H), 8.61 (d, J=5.7, 1H), 8.51 (d, J=2.3, 1H), 8.45 (d, J=5.7,1H), 8.16 (d, J=2.3, 1H), 7.35 (s, 2H), 7.25 (d, J=3.5, 1H), 6.98 (d,J=3.5, 1H), 3.68 (s, 2H), 3.60-3.57 (m, 4H), 2.86 (d, J=4.5, 3H), 2.44(m, 4H).

EXAMPLE 92-Amino-5-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamide(“A42”)

9.12-Amino-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-nicotinicacid

1.5 g1-[2-(tetrahydropyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-1H-pyrazoland 808 mg 2-amino-5-bromonicotinic acid are dissolved in 10 ml of DMF.3.3 g of potassium carbonate are added to the solution. The mixture isheated to 80° C. 395 mg of1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II),dichlormethane adduct are added and the mixture is heated for 2 h.

The solution is evaporated and the crude product is purified by silicagel chromatography using ethyl acetate/MeOH 9:1; 496 mg of2-Amino-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-nicotinicacid as a brown oil;

HPLC/MS: 1.27 min, [M+H]=333.

9.22-Amino-N-pyridin-4-yl-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-nicotinamide:

303 mg of2-Amino-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-nicotinicacid, 84 mg of 4-aminopyridine and 284 mg ofO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluorborate(TBTU) are dissolved in 10 ml of DMF. 0.15 ml of N-ethyldiisopropylamineand 21 mg of 4-(dimethylamino)-pyridine are added. The mixture isstirred over night at room temperature.

The reaction mixture is evaporated and purified by silica gelchromatography using dichloromethane/MeOH 9:1.

160 mg of2-Amino-N-pyridin-4-yl-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-nicotinamideare obtained as a yellow solid; HPLC/MS: 1.27 min, [M+H]=409.

9.32-Amino-5-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamide:

160 mg of2-Amino-N-pyridin-4-yl-5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-nicotinamideare dissolved in 4 ml of dichloromethane. 0.4 ml of HCl in dioxane (ca.4 mol/l) are added. After 1 h, the precipitate is filtered off andwashed with dichloromethane.

99 mg of2-Amino-5-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamideare obtained as yellow solid; HPLC/MS: 0.98 min, [M+H]=325;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.56 (s, 1H, NH), 8.50 (d, J=6.2,2H), 8.43 (d, J=2.2, 1H), 8.21 (d, J=2.3, 1H), 8.09 (s, 1H), 7.86 (s,1H), 7.76 (d, J=6.3, 2H), 6.94 (s, 2H), 4.90 (s, 1H, OH), 4.16 (t,J=5.6, 2H), 3.76 (d, J=4.8, 2H).

EXAMPLE 10

The following compounds are obtained analogously to example 1;

HPLC Method: A—0.1% TFA in H₂O, B—0.1% TFA in ACN: Flow—2.0 ml/min.

Column: X Bridge C8 (50×4.6 mm.3.5 μ).

2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-3-yl)-N-pyridin-4-yl-nicotinamide(“A43”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.53 (s, 1H), 8.53 (d, J=2.08 Hz,1H), 8.48 (d, J=5.00 Hz, 2H), 8.30 (d, J=2.12 Hz, 1H), 7.69-7.71 (m,3H), 7.44 (s, 1H), 7.07-7.12 (m, 2H), 3.69 (s, 2H), 3.57-3.59 (m, 4H),2.49-2.49 (m, 4H);

LCMS: Mass found (M+1, 396);

HPLC>97%, Rt (min): 1.362.

5-(4-Acetyl-1H-pyrrol-2-yl)-2-amino-N-pyridin-4-yl-nicotinamide (“A44”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.96 (s, 1H), 10.61 (s, 1H),8.48-8.53 (m, 1H), 8.47 (d, J=1.40 Hz, 2H), 8.40 (d, J=2.04 Hz, 1H),7.74 (dd, J=1.48, 4.90 Hz, 2H), 7.68 (dd, J=1.64, 2.88 Hz, 1H), 7.07 (s,2H), 6.85 (t, J=2.24 Hz, 1H), 2.34 (s, 3H);

LCMS: Mass found (M+1, 322);

HPLC>93%, RTL (min): 1.62.

2-Amino-5-furan-3-yl-N-pyridin-4-yl-nicotinamide (“A45”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.54 (s, 1H), 8.44-8.44 (m, 3H), 8.23(d, J=2.32 Hz, 1H), 8.12 (d, J=2.36 Hz, 1H), 7.74 (t, J=3.36 Hz, 1H),7.68 (d, J=4.64 Hz, 2H), 6.97-7.02 (m, 2H);

LCMS: Mass found (M+1, 281);

HPLC>96%, Rt (min): 1.64.

2-Amino-5-(1-benzyl-1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide (“A46”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.49 (s, 1H), 8.43-8.48 (m, 3H), 8.20(dd, J=2.28, 6.54 Hz, 2H), 7.90-7.91 (m, 2H), 7.69 (dd, J=1.52, 4.82 Hz,2H), 7.25-7.37 (m, 5H), 6.94 (s, 1H), 5.34 (s, 1H);

LCMS: Mass found (M+1, 371);

HPLC>98%, Rt (min): 2.34.

2-Amino-5-(1-methyl-1H-pyrazol-3-yl)-N-pyridin-4-yl-nicotinamide (“A47”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.65 (s, 1H), 8.59 (d, J=2.20 Hz,1H), 8.48 (d, J=6.20 Hz, 2H), 8.36 (d, J=2.20 Hz, 1H), 7.73 (dd, J=2.12,4.42 Hz, 3H), 7.07 (s, 1H), 6.66 (d, J=2.24 Hz, 1H), 3.87 (s, 3H);

LCMS: Mass found (M+1, 295);

HPLC>99%, Rt (min): 1.46.

2-Amino-5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide(“A48”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 12.29 (s, 1H), 10.36 (s, 1H), 8.45 (d,J=5.24 Hz, 2H), 8.09 (d, J=2.00 Hz, 1H), 8.00 (d, J=2.00 Hz, 1H), 7.70(d, J=6.24 Hz, 2H), 7.01 (s, 1H), 2.16 (s, 6H);

LCMS: Mass found (M+1, 309);

HPLC>99%, Rt (min): 3.71.

2-Amino-N-pyridin-4-yl-5-thiophen-3-yl-nicotinamide (“A49”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.53 (s, 1H), 8.57 (d, J=2.28 Hz,1H), 8.47 (d, J=6.24 Hz, 2H), 8.35 (d, J=2.28 Hz, 1H), 7.80-7.81 (m,1H), 7.71 (dd, J=1.48, 4.86 Hz, 2H), 7.66 (dd, J=2.92, 5.00 Hz, 1H),7.59 (dd, J=1.20, 5.00 Hz, 1H), 7.09 (s, 2H);

LCMS: Mass found (M+1, 297);

HPLC>95%, Rt (min): 1.88.

2-Amino-5-(1-methyl-1H-pyrrol-2-yl)-N-pyridin-4-yl-nicotinamide (“A50”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.45 (s, 1H), 8.46 (d, J=6.12 Hz,2H), 8.24 (d, J=2.16 Hz, 1H), 8.14 (d, J=2.12 Hz, 1H), 7.71 (d, J=6.32Hz, 2H), 7.13 (s, 2H), 6.83 (t, J=2.00 Hz, 1H), 6.16 (dd, J=1.84, 3.52Hz, 1H), 6.05-6.07 (m, 1H), 3.60 (s, 3H);

LCMS: Mass found (M+1, 294);

HPLC>95%, Rt (min): 1.84.

2-Amino-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamide(“A51”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.51 (s, 1H), 8.47 (dd, J=1.48, 4.82Hz, 2H), 8.42 (dd, J=2.24, Hz, 1H), 8.18 (dd, J=2.24, Hz, 1H), 8.12 (s,1H), 7.84-7.85 (m, 1H), 7.70 (dd, J=1.52, 4.80 Hz, 2H), 6.92 (s, 2H),4.23 (t, J=6.64 Hz, 2H), 3.54 (t, J=4.68 Hz, 4H), 2.73 (t, J=6.64 Hz,2H), 2.41 (t, J=4.40 Hz, 4H);

LCMS: Mass found (M+1, 394);

HPLC>99%, Rt (min): 3.84

2-Amino-5-benzo[b]thiophen-2-yl-N-pyridin-4-yl-nicotinamide (“A52”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.41 (s, 1H), 8.73 (d, J=6.52 Hz,2H), 8.65 (d, J=2.32 Hz, 1H), 8.15 (s, 1H), 8.15 (d, J=6.88 Hz, 2H),7.97 (d, J=7.52 Hz, 1H), 7.79-7.82 (m, 2H), 7.32-7.43 (m, 4H);

LCMS: Mass found (M+1, 347);

HPLC>94%, Rt (min): 2.87.

5-(5-Acetyl-thiophen-2-yl)-2-amino-N-pyridin-4-yl-nicotinamide (“A53”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.62 (s, 1H), 8.60 (d, J=2.40 Hz,1H), 8.49 (dd, J=1.40, 4.86 Hz, 2H), 8.37 (d, J=2.40 Hz, 1H), 7.95 (d,J=4.00 Hz, 1H), 7.71 (dd, J=1.56, 4.82 Hz, 2H), 7.59 (d, J=3.96 Hz, 1H),7.39 (s, 2H), 2.48 (s, 3H)

LCMS: Mass found (M+1, 339);

HPLC>96%, Rt (min): 2.01.

2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-N-pyridin-4-yl-nicotinamide(“A54”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 8.27-8.34 (m, 3H), 7.60 (s, 2H), 7.06(d, J=3.64 Hz, 1H), 6.93 (d, J=3.36 Hz, 1H), 3.65 (s, 2H), 3.58 (t,J=4.48 Hz, 4H), 2.41-2.49 (m, 4H), 1.50 (s, 3H);

LCMS: Mass found (M+1, 396);

HPLC>98%, Rt (min): 1.39.

2-Amino-5-(1H-indol-2-yl)-N-pyridin-4-yl-nicotinamide (“A55”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.43 (s, 1H), 10.63 (s, 1H), 8.69 (d,J=2.04 Hz, 1H), 8.47-8.49 (m, 3H), 7.73 (d, J=5.12 Hz, 2H), 7.50 (d,J=7.64 Hz, 1H), 7.37 (d, J=7.96 Hz, 1H), 7.13 (s, 2H), 6.83-7.08 (m,3H);

LCMS: Mass found (M+1, 330);

HPLC>99%, Rt (min): 2.60.

2-Amino-5-(1H-indol-3-yl)-N-pyridin-4-yl-nicotinamide (“A56”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.33 (s, 1H), 10.55 (s, 1H),8.46-8.51 (m, 3H), 8.30 (d, J=2.28 Hz, 2H), 7.83 (d, J=7.92 Hz, 1H),7.67-7.82 (m, 2H), 7.44 (d, J=8.00 Hz, 1H), 7.05-7.16 (m, 2H), 6.93 (s,2H);

LCMS: Mass found (M+1, 330);

HPLC>93%, Rt (min): 2.23.

2-Amino-N-pyridin-4-yl-5-(1H-pyrrol-2-yl)-nicotinamide (“A57”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 11.15 (s, 1H), 10.54 (s, 1H),8.46-8.48 (m, 3H), 8.22 (d, J=2.28 Hz, 1H), 7.71 (dd, J=1.52, 4.86 Hz,2H), 6.89 (s, 2H), 6.82 (dd, J=2.56, 4.02 Hz, 1H), 6.42 (t, J=3.60 Hz,1H), 6.10 (dd, J=2.52, 5.66 Hz, 1H),

LCMS: Mass found (M+1, 280);

HPLC>94%, Rt (min): 1.71.

2-Amino-5-(1H-imidazo[1,2-a]pyridin-2-yl)-N-pyridin-4-yl-nicotinamide(“A58”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.46 (s, 1H), 8.55 (d, J=6.88 Hz,1H), 8.47 (d, J=6.04 Hz, 2H), 8.41 (d, J=2.12 Hz, 1H), 8.35 (d, J=2.00Hz, 1H), 7.79 (s, 1H), 7.74-7.77 (m, 2H), 7.63-7.65 (m, 1H), 7.26-7.30(m, 3H), 6.92-6.94 (m, 1H).

LCMS: Mass found (M+1, 331);

HPLC>91%, Rt (min): 3.68.

2-Amino-N-pyridin-4-yl-5-(1H-pyrrol-3-yl)-nicotinamide (“A59”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.90 (s, 1H), 10.50 (s, 1H), 8.47(dd, J=1.52, 4.80 Hz, 2H), 8.40 (dd, J=2.24, Hz, 1H), 8.15 (dd, J=2.28,Hz, 1H), 7.72 (dd, J=1.52, 4.78 Hz, 2H), 7.18 (dd, J=1.88, 4.20 Hz, 1H),6.79-6.82 (m, 3H), 6.43-6.45 (m, 1H);

LCMS: Mass found (M+1, 280);

HPLC>98%, Rt (min): 1.43.

2-Amino-5-benzofuran-3-yl-N-pyridin-4-yl-nicotinamide (“A60”)

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 10.58 (s, 1H), 8.54-8.55 (m, 3H),8.33-8.36 (m, 2H), 7.95-7.97 (m, 1H), 7.72 (d, J=3.44 Hz, 2H), 7.65-7.65(m, 1H), 7.32-7.41 (m, 2H), 7.13 (s, 2H);

LCMS: Mass found (M+1, 331);

HPLC>93%, Rt (min): 2.50.

2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide (“A61”)

EXAMPLE 11

LC-MS Conditions

Hewlett Packard HP 1200 series system with the following features: ionsource: electrospray (positive mode); scan: 100-1000 m/e; fragmentationvoltage: 100 V; gas temperature: 350° C., UV: 220 nm.

Method 1

HPLC/MS conditions:

-   column: Chromolith SpeedROD RP-18e, 50-4.6-   gradient: A:B=96:4 to 0:100    -   4% B→100% B: 0 min bis 2.8 min    -   100% B: 2.8 min bis 3.3 min    -   100% B→4% B: 3.3 min bis 4 min-   flow rate: 2.4 ml/min-   eluent A: water+0.05% formic acid-   eluent B: acetonitrile+0.04% formic acid-   wavelength: 220 nm-   mass spectroscopy: positive mode    Method 2

HPLC/MS conditions:

-   column: Chromolith SpeedROD RP-18e, 50-4.6-   gradient: A:B=100:0 to 0:100    -   0% B→0% B: 0 min bis 0.5 min    -   0% B→100% B 0.5 min bis 2.6 min    -   100% B: 2.6 min bis 3.0 min    -   100% B→0%B: 3.0 min bis 3.1 min-   flow rate: 2.4 ml/min-   eluent A: water+0.05% formic acid-   eluent B: acetonitrile+0.04% formic acid-   wavelength: 220 nm-   mass spectroscopy: positive mode

2-Amino-5-(3-hydroxymethyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A62”)

100 mg of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide and 62.2 mg3-hydroxy-methyl)-benzeneboronic acid are dissolved in 4 ml of DMF. 90.4mg Na₂CO₃ and 1 ml water are added under argon. 13.9 mg of[1,1-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) are added.The mixture is stirred for 14 h at 100° C.

The reaction mixture is cooled to room temperature and the DMF isevaporated and the product was purified by chromatography.

45 mg of “A62” are obtained; method 1: HPLC/MS: 1.11 min, [M+H]=321;

¹H NMR (400 MHz, DMSO-d₆) δ [ppm] 9.01 (1 H, d, J 2.2), 8.88-8.83 (2 H,m), 8.67 (1 H, d, J 2.3), 8.34-8.29 (2 H, m), 7.79 (1 H, s), 7.69 (1 H,d, J 7.6), 7.52 (1 H, t, J 7.6), 7.46 (1 H, d, J 7.8), 4.65 (2 H, s).

The following compounds are obtained analogously:

2-Amino-5-(2-hydroxymethyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A63”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with2-(hydroxymethyl)-benzeneboronic acid gives “A63”; method 1: HPLC/MS:1.07 min, [M+H]=321;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.88 (1 H, d, J 2.1), 8.81 (2H, d, J 7.2), 8.52 (1 H, d, J 2.1), 8.31 (2 H, d, J 7.3), 7.63 (1 H, d,J 7.3), 7.53-7.44 (3 H, m), 4.52 (2 H, s);

2-Amino-5-(2-tert-butylsulfamoyl-phenyl)-N-pyridin-4-yl-nicotinamide(“A64”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with2-tert.-butyl-sulfamoyl-benzeneboronic acid gives “A64”; method 1:HPLC/MS: 1.41 min, [M+H]=426;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.86-8.80 (3 H, m), 8.39 (1 H,d, J 2.1), 8.28 (2 H, d, J 7.3), 8.15 (1 H, dd, J 7.9, 1.2), 7.73 (2 H,dtd, J 31.4, 7.6, 1.4), 7.57 (1 H, dd, J 7.6, 1.2), 1.09 (9 H, s);

2-Amino-5-(4-amino-phenyl)-N-pyridin-4-yl-nicotinamide (“A65”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-aminophenyl-boronic acid hydrochloride gives “A65”; method 2: HPLC/MS:1.53 min, [M+H]=306;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.05 (1 H, d, J 2.2), 8.87 (2H, d, J 7.5), 8.72 (1 H, d, J 2.2), 8.36 (2 H, d, J 7.3), 7.99 (2 H, d,J 8.5), 7.60-7.55 (2 H, m);

2-Amino-5-(2-formyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A66”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with2-formylphenyl-boronic acid gives “A66”; method 1: HPLC/MS: 1.23 min,[M+H]=319;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 10.08 (1 H, s), 8.88 (1 H, d, J2.2), 8.81 (2 H, d, J 7.3), 8.51 (1 H, d, J 2.2), 8.32-8.28 (2 H, m),8.11-8.07 (1 H, m), 7.83 (1 H, td, J 7.6, 1.5), 7.72 (1 H, t, J 7.2),7.64 (1 H, dd, J 7.6, 0.9);

3-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid ethylester (“A67”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with3-ethoxycarbonyl-phenylboronic acid gives “A67”; method 1: HPLC/MS: 1.48min, [M+H]=363;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.06 (1 H, d, J 2.2), 8.85 (2H, d, J 7.3), 8.76 (1 H, d, J 2.2), 8.41 (1 H, t, J 1.7), 8.33 (2 H, d,J 7.3), 8.13-8.03 (2 H, m), 7.70 (1 H, t, J 7.8), 4.41 (2 H, q, J 7.1),1.39 (3 H, t, J 7.1);

2-Amino-5-(4-hydroxymethyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A68”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-(hydroxymethyl)-phenylboronic acid; method 1: HPLC/MS: 1.12 min,[M+H]=321;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.02 (1 H, d, J 2.2), 8.83 (2H, d, J 7.3), 8.65 (1 H, d, J 2.2), 8.33 (2 H, d, J7.3), 7.79 (2 H, d, J8.2), 7.54 (2 H, d, J 8.4), 4.63 (2 H, s);

2-Amino-5-(3-hydroxy-phenyl)-N-pyridin-4-yl-nicotinamide (“A69”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with3-hydroxyphenyl-boronic acid pinacol ester gives “A70”; method 1:HPLC/MS: 1.12 min, [M+H]=307.

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.02 (1 H, d, J 2.2), 8.82 (2H, d, J 5.1), 8.62 (1 H, s), 8.34 (2 H, d, J 7.3), 7.36 (1 H, t, J 7.8),7.22 (2 H, d, J 8.1), 6.96 (1 H, dd, J 7.5, 1.8);

2-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid ethylester (“A70”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide withethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate gives“A70”; method 1: HPLC/MS: 1.37 min, [M+H]=363;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.86 (1 H, d, J 2.1), 8.79 (2H, d, J 7.1), 8.40 (1 H, d, J 2.0), 8.32 (2 H, d, J 7.3), 8.12 (1 H, dd,J 7.8, 0.9), 7.75 (1 H, td, J 7.6, 1.1), 7.64 (1 H, td, J 7.7, 0.9),7.57 (1 H, d, J 7.5), 4.23 (2 H, q, J 7.1), 1.22 (3 H, t);

4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid ethylester (“A71”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-ethoxycarbonyl-phenylboronic acid gives “A71”; method 1: HPLC/MS: 1.46min, [M+H]=363;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.08 (1 H, d, J 2.2), 8.84 (2H, d, J 7.2), 8.77 (1 H, d, J 2.1), 8.33 (2 H, d, J 7.2), 8.17 (2 H, d,J 8.5), 7.97 (2 H, d, J 8.4), 4.38 (2 H, q, J 7.1), 1.38 (3 H, t, J7.1);

2-Amino-5-(4-hydroxy-phenyl)-N-pyridin-4-yl-nicotinamide (“A72”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-hydroxybenzene-boronic acid gives “A72”; method 1: HPLC/MS: 1.07 min,[M+H]=307;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.99 (1 H, d, J 2.1), 8.78 (2H, dd, J 7.2, 2.4), 8.51 (1 H, t, J 2.1), 8.35 (2 H, d, J 7.2), 7.61 (2H, dd, J 8.5, 1.8), 7.01 (2 H, d, J 8.6);

2-Amino-5-(2-hydroxy-phenyl)-N-pyridin-4-yl-nicotinamide (“A73”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol gives “A73”;method 1: HPLC/MS: 1.16 min, [M+H]=307;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.95 (1 H, d, J 2.1), 8.83 (2H, d, J 7.2), 8.62 (1 H, d, J 2.1), 8.30 (2 H, d, J 7.2), 7.53 (1 H, dd,J 7.7, 1.5), 7.32-7.27 (1 H, m), 7.11-7.07 (1 H, m), 7.03-6.98 (1 H, m);

2-Amino-5-(3-formyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A74”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with3-formylbenzene-boronic acid gives “A75”; method 1: HPLC/MS: 1.29 min,[M+H]=319;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 10.13 (1 H, s), 9.13 (1 H, d, J2.2), 8.83-8.75 (3 H, m), 8.36 (3 H, d, J 7.2), 8.14-8.02 (2 H, m), 7.78(1 H, t, J 7.7);

2-Amino-5-(4-formyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A75”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-formylbenzene-boronic acid gives “A75”; method 1: HPLC/MS: 1.29 min,[M+H]=319;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 10.10 (1 H, s), 9.08 (1 H, d, J2.2), 8.86 (2 H, d, J 7.2), 8.82 (1 H, d, J 2.2), 8.32 (2 H, d, J 7.3),8.12-8.05 (4 H, m);

2-Amino-5-(3-aminomethyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A76”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with3-aminomethyl-phenylboronic acid hydrochloride gives “A76”; method 1:HPLC/MS: 0.94 min, [M+H]=320;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.99 (1 H, d, J 2.3), 8.86 (2H, d, J 7.3), 8.65 (1 H, d, J 2.2), 8.31 (2 H, d, J 7.3), 7.93 (1 H, s),7.87 (1 H, d, J 7.6), 7.61 (2 H, dt, J 15.7, 7.7), 4.17 (2 H, s);

2-Amino-5-(4-aminomethyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A77”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with4-aminomethyl-phenylboronic acid hydrochloride gives “A77”; method 1:HPLC/MS: 1.07 min, [M+H]=320;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.02 (1 H, d, J 2.2), 8.86 (2H, d, J 7.3), 8.73 (1 H, d, J 2.3), 8.31 (2 H, d, J 7.3), 7.91 (2 H, d,J 8.4), 7.67 (2 H, d, J 8.4), 4.15 (2 H, s);

2-Amino-N-pyridin-4-yl-5-(3-sulfamoyl-phenyl)-nicotinamide (“A78”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide withbenzenesulfon-amide-3-boronic acid pinacol ester gives “A78”; method 1:HPLC/MS: 1.13 min, [M+H]=370;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.01 (1 H, d, J 2.2), 8.86 (2H, d, J 7.3), 8.74 (1 H, d, J 2.3), 8.33-8.28 (3 H, m), 8.05 (1 H, d, J7.8), 7.98 (1 H, d, J 7.9), 7.77 (1 H, t, J 7.9);

2-Amino-5-[3-(4-hydroxy-piperidine-1-sulfonyl)-phenyl]-N-pyridin-4-yl-nicotinamide(“A79”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-piperidin-4-olgives “A79”; method 1: HPLC/MS: 1.29 min, [M+H]=454;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.01 (1 H, d, J 2.3), 8.86 (2H, d, J 7.3), 8.80 (1 H, d, J 2.2), 8.30 (2 H, d, J 7.3), 8.19-8.13 (2H, m), 7.87-7.80 (2 H, m), 3.64-3.57 (1 H, m), 3.25-3.17 (2 H, m),2.93-2.89 (2 H, m), 1.83-1.75 (2 H, m), 1.58-1.44 (2 H, m);

4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-2-fluoro-benzoic acidmethyl ester (“A80”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with3-fluoro-4-methoxycarbonyl-phenylboronic acid gives “A80”; method 1:HPLC/MS: 1.48 min, [M+H]=367;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.10 (1 H, d, J 2.2), 8.84 (3H, t, J 4.8, 2.5), 8.34 (2 H, d, J 7.3), 8.09 (1 H, t, J 8.0), 7.87 (1H, dd, J 12.2, 1.6), 7.80 (1 H, dd, J 8.2, 1.7), 3.92 (3H, s);

{2-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-phenyl}-carbamicacid tert.-butyl ester (“A81”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acidtert-butyl ester gives “A81”; method 1: HPLC/MS: 1.38 min, [M+H]=406;

{3-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-phenyl}-carbamicacid tert.-butyl ester (“A82”)

Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with3-(N-Boc-amino)phenylboronic acid gives “A82”; method 1: HPLC/MS: 1.56min, [M+H]=406.

EXAMPLE 122-Amino-5-{4-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A83”)

12.1 4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid(“A31”)

A solution of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid ethyl ester (290 mg, 0.08 mmol), THF (5 mL) and 1N NaOH (4 mL,25.0) is stirred at room temperature for 14 h. The THF is removed invacuo and the mixture acidified with 1N HCl.

The resulting precipitate is filtered off, washed with water and dried.260 mg of the desired product are obtained as a white solid; method 1:HPLC/MS: 1.21 min, [M+H]=335;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.13 (1 H, s), 8.93-8.70 (4 H,m), 8.38 (2 H, d, J 6.6), 7.97 (2 H, d, J 8.4), 7.83 (1 H, d, J 8.5).

Using the above mentioned procedure the following compounds are obtainedanalogously:

3-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid (“A84”)

Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid ethyl ester gives “A84”; method 1: HPLC/MS: 1.21 min, [M+H]=335;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.12 (1 H, d, J 2.2), 8.85 (2H, d, J 7.2), 8.78 (1 H, d, J 2.2), 8.44 (1 H, s), 8.37 (2 H, d, J 7.2),8.10 (2 H, d, J 7.9), 7.68 (1 H, t, J 7.8);

2-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid (“A85”)

Reaction of 2-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid ethyl ester gives “A85”; method 1: HPLC/MS: 1.15 min, [M+H]=335;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.86 (1 H, d, J 2.1), 8.79 (2H, d, J 7.1), 8.40 (1 H, d, J 2.0), 8.32 (2 H, d, J 7.3), 8.12 (1 H, dd,J 7.8, 0.9), 7.75 (1 H, td, J 7.6, 1.1), 7.64 (1 H, td, J 7.7, 0.9),7.57 (1 H, d, J 7.5);

4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-2-fluoro-benzoic acid(“A86”)

Reaction of4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-2-fluoro-benzoic acidmethyl ester gives “A86”; method 1: HPLC/MS: 1.22 min, [M+H]=353;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.13 (1 H, d, J 2.2), 8.83 (3H, t, J 4.7), 8.37 (2 H, d, J 7.4), 8.10 (1 H, t, J 8.0), 7.85 (1 H, dd,J 12.1, 1.7), 7.78 (1 H, dd, J 8.2, 1.7).

12.22-Amino-5-{4-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A83”)

60 mg (0.18 mmol) of4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid and23.13 μl (0.22 mmol) of N-(methoxyethyl)methylamine are dissolved in 2mL DMF. 102.36 mg HATU((2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate) and 59.19 μL N-methylmorpholine are added to thesolution. The mixture is stirred for 3 h at room temperature. The DMF isevaporated and the product is purified by chromatography.

16 mg of “A83” are obtained; method 1: HPLC/MS: 1.22 min, [M+H]=406;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.05 (1 H, d, J 2.2), 8.86 (2H, d, J 7.3), 8.74 (1 H, d, J 2.2), 8.31 (2 H, d, J 7.3), 7.89 (2 H, d,J 8.0), 7.60 (2 H, d, J 8.3), 3.75-3.57 (2 H, m), 3.53-3.41 (3 H, m),3.38-3.19 (2 H, m), 3.04 (3 H, s).

Using the above mentioned procedure the following compounds are obtainedanalogously:

2-Amino-5-(4-diethylcarbamoyl-phenyl)-N-pyridin-4-yl-nicotinamide(“A87”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with diethyl amine gives “A87”; method 1: HPLC/MS: 1.36 min,[M+H]=390;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.05 (1 H, d, J 2.3), 8.86 (2H, d, J 7.3), 8.74 (1 H, d, J 2.2), 8.31 (2 H, d, J 7.3), 7.90 (2 H, d,J 8.4), 7.55 (2 H, d, J 8.3), 3.60-3.17 (4 H, m), 1.29-1.00 (6 H, m);

2-Amino-5-(4-carbamoyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A88”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with ammonia gives “A88”; method 1: HPLC/MS: 1.10 min, [M+H]=334;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.06 (1 H, d, J 2.2), 8.86 (2H, d, J 7.2), 8.77 (1 H, d, J 2.2), 8.31 (2 H, d, J 7.2), 8.11 (2 H, d,J 8.4), 7.94 (2 H, d, J 8.4);

2-Amino-5-{4-[bis-(2-methoxy-ethyl)-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A89”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with bis-(2-methoxy-ethyl)-amine gives “A89”; method 1: HPLC/MS:1.30 min, [M+H]=450;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.08 (1 H, d, J 2.2), 8.83 (2H, d, J 7.2), 8.72 (1 H, d, J 2.1), 8.34 (2 H, d, J 7.3), 7.88 (2 H, d,J 8.2), 7.59 (2 H, d, J 8.3), 3.73-3.26 (14 H, m);

2-Amino-5-{4-[(2-dimethylamino-ethyl)-methyl-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A90”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with N,N,N′-trimethylethylenediamine gives “A90”; method 2:HPLC/MS: 1.55 min, [M+H]419;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.08 (1 H, d, J 2.1), 8.80 (2H, dd, J 7.3, 1.1), 8.71 (1 H, d, J 2.0), 8.35 (2 H, d, J 7.3), 7.91 (2H, d, J 8.1), 7.69 (2 H, d, J 8.1), 3.90 (2 H, t), 3.46 (2 H, t), 3.05(3 H, s), 2.95 (6 H, s);

2-Amino-5-{4-[(2-dimethylamino-ethyl)-ethyl-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A91”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with N′-ethyl-N,N-dimethyl-ethane-1,2-diamine gives “A91”; method1: HPLC/MS: 1.08 min, [M+H]=433;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.09 (1 H, d, J 2.2), 8.80 (2H, d, J 7.3), 8.71 (1 H, d, J 2.2), 8.36 (2 H, d, J 7.4), 7.91 (2 H, d,J 8.3), 7.64 (2 H, d, J 8.3), 3.86 (2 H, t), 3.44 (2 H, t, J 6.4),3.41-3.27 (2 H, m), 2.98 (6 H, s), 1.14 (3 H, t, J 6.6);

2-Amino-5-[4-(2-methoxy-ethylcarbamoyl)-phenyl]-N-pyridin-4-yl-nicotinamide(“A92”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with 2-methoxy-ethylamine gives “A92”; method 1: HPLC/MS: 1.25 min,[M+H]=392;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.10 (1 H, d, J 2.2), 8.81 (2H, d, J 7.3), 8.74 (1 H, d, J 2.2), 8.35 (2 H, d, J 7.4), 8.11 (2 H, d,J 8.5), 7.91 (2 H, d, J 8.5), 3.55 (4 H, s), 3.34 (3 H, s);

2-Amino-5-{4-[bis-(2-hydroxy-ethyl)-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A93”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with 2-(2-hydroxy-ethylamino)-ethanol gives “A93”; method 2:HPLC/MS: 1.62 min, [M+H]=422;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.57 (1 H, d, J 2.3), 8.49 (2 H, dd, J4.8, 1.5), 8.39 (1 H, d, J 2.3), 7.77 (2 H, d, J 8.3), 7.73 (2 H, dd, J4.8, 1.5), 7.49 (2 H, d, J 8.3), 3.64-3.46 (8 H, m);

2-Amino-5-[4-(3-methoxy-propylcarbamoyl)-phenyl]-N-pyridin-4-yl-nicotinamide(“A94”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with 3-methoxy-propylamine gives “A94”; method 1: HPLC/MS: 1.30min, [M+H]=406;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.11 (1 H, d, J 2.2), 8.76 (2H, d), 8.69 (1 H, d, J 2.1), 8.37 (2 H, d, J 7.3), 8.07 (2 H, d, J 3.3),7.88 (2 H, d, J 8.4), 3.48-3.45 (4 H, m), 3.31 (3 H, s), 1.88 (2 H, p, J6.5);

2-Amino-5-{4-[methyl-(3-methyl-3H-imidazol-4-ylmethyl)-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A95”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with methyl-(3-methyl-3H-imidazol-4-ylmethyl)-amine gives “A95”;method 1: HPLC/MS: 1.07 min, [M+H]=442;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.09 (1 H, s), 9.08 (1 H, d, J2.1), 8.79 (2 H, d, J 7.3), 8.70 (1 H, d, J 2.0), 8.35 (2 H, d, J 7.3),7.89 (2 H, d, J 8.3), 7.71 (1 H, s), 7.68 (2 H, d, J 8.3), 3.97 (2 H,s), 3.00 (3 H, s), 2.79 (3 H, s);

2-{4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoylamino}-ethylcarbamic acid tert.-butyl ester (“A96”)

Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with (2-amino-ethyl)-carbamic acid tert-butyl ester gives “A96”;method 1: HPLC/MS: 1.47 min, [M+H]=477;

2-Amino-5-{3-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A97”)

Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with N-(methoxy-ethyl)-methyl-amine gives “A97”; method 1: HPLC/MS:1.23 min, [M+H]=406;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.03 (1 H, s), 8.86 (2 H, d, J7.3), 8.74 (1 H, s), 8.31 (2 H, d, J 7.4), 7.88 (2 H, d, J 1.6), 7.62 (1H, t, J 7.9), 7.49 (1 H, d, J 7.7), 3.73-2.96 (10 H, m);

2-Amino-5-(3-diethylcarbamoyl-phenyl)-N-pyridin-4-yl-nicotin-amide(“A98”)

Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with diethyl amine gives “A98”; method 1: HPLC/MS: 1.37 min,[M+H]=390;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.04 (1 H, d, J 2.1), 8.85 (2H, d, J 7.2), 8.74 (1 H, d, J 2.1), 8.31 (2 H, d, J 7.2), 7.89 (1H, d, J8.1), 7.84 (1H, s), 7.62 (1 H, t, J 7.7), 7.45 (1 H, d, J 7.5),3.57-3.23 (4 H, m), 1.28-1.01 (6 H, m);

2-Amino-5-(3-carbamoyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A99”)

Reaction of 3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with ammonia gives “A99”; method 2: HPLC/MS: 1.64 min, [M+H]=334.

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.07 (1 H, d, J 2.2), 8.85 (2H, d, J 7.3), 8.76 (1 H, d, J 2.2), 8.36 (1 H, t, J 1.7), 8.32 (2 H, d,J 7.3), 8.00 (2 H, td, J 8.3, 1.6), 7.65 (1 H, t, J 7.8);

2-Amino-5-(2-diethylcarbamoyl-phenyl)-N-pyridin-4-yl-nicotin-amide(“A100”)

Reaction of 2-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with diethyl amine gives “A100”; method 2: HPLC/MS: 1.35 min,[M+H]=390;

¹H NMR (500 MHz, DMSO-d₆) δ [ppm] 8.83 (2 H, d, J 7.3), 8.81 (1 H, d, J2.2), 8.35 (1 H, d, J 2.1), 8.31 (2 H, d, J 7.3), 7.70-7.67 (1 H, m),7.62 (1 H, td, J 7.6, 1.3), 7.56 (1 H, ddd, J 6.0, 5.5, 1.4), 7.45 (1 H,dd, J 7.5, 1.1), 3.47-3.30 (2 H, m), 3.03 (2 H, q, J 7.0), 1.02-0.91 (3H, m);

2-Amino-5-(2-carbamoyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A101”)

Reaction of 2-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid with ammonia gives “A101”; method 1: HPLC/MS: 1.05 min, [M+H]=334;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.86 (1 H, d, J 2.1), 8.79 (2H, d, J 7.1), 8.40 (1 H, d, J 2.0), 8.32 (2 H, d, J 7.3), 8.12 (1 H, dd,J 7.8, 0.9), 7.75 (1 H, td, J 7.6, 1.1), 7.64 (1 H, td, J 7.7, 0.9),7.57 (1 H, d, J 7.5);

2-Amino-5-{3-fluoro-4-[(2-methoxy-ethyl)-methyl-carbamoyl]-phenyl}-N-pyridin-4-yl-nicotinamide(“A102”)

Reaction of4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-2-fluoro-benzoic acidwith N-(methoxyethyl)-methylamine gives “A102”; method 1: HPLC/MS: 1.34min, [M+H]=424;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.09 (1 H, d, J 2.0), 8.81 (2H, d, J 7.2), 8.76 (1 H, d, J 2.2), 8.35 (2 H, d, J 7.3), 8.08 (1 H, s),7.82-7.69 (1 H, m), 7.57 (1 H, td, J 7.6, 2.9), 3.72 (1 H, t, J 5.5),3.63 (1 H, t, J 5.5), 3.43 (2 H, dd, J 10.0, 4.1), 3.36 (2 H, s), 3.23(1 H, s), 3.10 (2 H, s), 2.97 (1 H, s);

EXAMPLE 13 2-Amino-5-(2-amino-phenyl)-N-pyridin-4-yl-nicotinamide(“A103”)

13.1 2-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-phenyl-carbamicacid tert.-butyl ester

The title compound is obtained from2-amino-5-bromo-N-(2-ethoxy-pyridin-4-yl)-nicotinamide and[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acidtert.-butyl ester analogously to the preparation of “A62”; method 1:HPLC/MS: 1.34 min, [M+H]=406.

13.2 2-Amino-5-(2-amino-phenyl)-N-pyridin-4-yl-nicotinamide

100 mg of{2-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-phenyl}-carbamicacid tert.-butyl ester are dissolved in 2 ml dichloromethane. 0.5 ml ofHCl in dioxane (4 molar) are added. The mixture is stirred 2 h at roomtemperature. The mixture is filtered and the solid washed withdichloromethane. 80 mg of “A103”, hydrochloride salt, are obtained;method 1: HPLC/MS: 1.17 min, [M+H]=306;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.99 (1 H, d, J 2.2), 8.85 (2H, d, J 7.3), 8.49 (1 H, d, J 2.1), 8.43 (2 H, d, J 7.5), 7.68-7.55 (4H, m).

Using the above mentioned procedure the following compounds are obtainedanalogously:

2-Amino-5-(3-amino-phenyl)-N-pyridin-4-yl-nicotinamide (“A104”)

Solvolysis of{3-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-phenyl}-carbamicacid tert.-butyl ester gives “A104”; method 1: HPLC/MS: 0.99 min,[M+H]=306;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.02 (1 H, d, J 2.2), 8.86 (2H, d, J 7.3), 8.69 (1 H, d, J 2.2), 8.37 (2 H, d, J 7.3), 7.94 (1 H, d,J 8.1), 7.86 (1 H, t, J 1.8), 7.70 (1 H, t, J 7.9), 7.54 (1 H, dd, J8.0, 1.2);

2-Amino-5-[4-(2-amino-ethylcarbamoyl)-phenyl]-N-pyridin-4-yl-nicotinamide(“A105”)

Solvolysis of(2-{4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoylamino}-ethyl)-carbamicacid tert.-butyl ester gives “A105”; method 2: HPLC/MS: 1.57 min,[M+H]=377;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.18 (1 H, d, J 2.2), 8.77 (2H, d, J 7.3), 8.72 (1 H, d, J 2.2), 8.42 (2 H, d, J 7.3), 8.13 (2 H, d,J 8.4), 7.96 (2 H, d, J 8.5), 3.67 (2 H, t, J 10.6, 4.6), 3.14 (2 H, t,J 5.8).

EXAMPLE 14 2-Amino-N-pyridin-4-yl-5-(2-sulfamoyl-phenyl)-nicotinamide(“A106”)

14.12-Amino-5-(2-tert.-butylsulfamoyl-phenyl)-N-pyridin-4-yl-nicotin-amide

The compound is obtained by reaction of2-amino-5-bromo-N-(2-ethoxy-pyridin-4-yl)-nicotinamide with2-tert.-butylsulfamoyl-benzeneboronic acid analogously to step 1 for“A62”; method 1: HPLC/MS: 1.41 min, [M+H]=426;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.86-8.80 (3 H, m), 8.39 (1 H,d, J 2.1), 8.28 (2 H, d, J 7.3), 8.15 (1 H, dd, J 7.9, 1.2), 7.73 (2 H,dtd, J 31.4, 7.6, 1.4), 7.57 (1 H, dd, J 7.6, 1.2), 1.09 (9 H, s).

14.2 2-Amino-N-pyridin-4-yl-5-(2-sulfamoyl-phenyl)-nicotinamide (“A106”)

20 mg2-Amino-5-(2-tert.-butylsulfamoyl-phenyl)-N-pyridin-4-yl-nicotinamide isdissolved in 0.5 ml of trifluoroacetic acid. The mixture is stirred at80° C. for 14 h. The reaction mixture is cooled to room temperature, 2ml heptan is added and the solvent is removed in vacuo, the residue isdissolved in methylene chloride and the resulting precipitate isfiltered off, to give 17 mg “A106” as trifluoro-acetate salt; method 1:HPLC/MS: 1.07 min, [M+H]=370;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.86 (1 H, d, J 2.2), 8.82 (2H, d, J 7.3), 8.42 (1 H, d, J 2.2), 8.33 (2 H, d, J 7.5), 8.18 (1 H, dd,J 7.8, 1.4), 7.73 (2H, dtd, J 22.4, 7.6, 1.4), 7.58 (1 H, dd, J 7.4,1.4).

EXAMPLE 152-Amino-5-[4-(tert-butylamino-methyl)-phenyl]-N-pyridin-4-yl-nicotinamide(“A107”)

15.1 2-Amino-5-(4-formyl-phenyl)-N-pyridin-4-yl-nicotinamide

The title compound is obtained by reaction of2-amino-5-bromo-N-(2-ethoxy-pyridin-4-yl)-nicotinamide with4-formylbenzeneboronic acid analogously to step 1 for “A62”; method 1:HPLC/MS: 1.29 min, [M+H]=319;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 10.10 (1 H, s), 9.08 (1 H, d, J2.2), 8.86 (2 H, d, J 7.2), 8.82 (1 H, d, J 2.2), 8.32 (2 H, d, J 7.3),8.12-8.05 (4 H, m).

15.22-Amino-5-[4-(tert-butylamino-methyl)-phenyl]-N-pyridin-4-yl-nicotinamide(“A107”)

70 mg NaB(OAc)₃H is added to a mixture of 50 mg2-amino-5-(4-formyl-phenyl)-N-pyridin-4-yl-nicotinamide, 20.6 μltert.-butylamine and 9 μl acetic acid in 0.5 ml 1,2-dichloroethane and0.5 ml tetrahydrofuran. The resulting suspension is stirred at 50° C.for 14 h. The reaction mixture is made basic with a 2N NaOH solution andextracted with dichloromethane. The organic layer is washed with brine,then separated and dried over Na₂SO₄. The drying agent is filtered andthe solvent is removed in vacuo. The product is purified bychromatography to yield 10 mg “A107” as a white solid; method 1:HPLC/MS: 1.10 min, [M+H]=376;

¹H NMR (400 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 9.05 (1 H, d, J 2.2), 8.84 (2H, d, J 7.3), 8.75 (1 H, d, J 2.2), 8.34 (2 H, d, J 7.3), 7.94 (2 H, d,J 8.4), 7.73 (2 H, d, J 8.4), 4.20 (2 H, s), 1.44 (9 H, s).

EXAMPLE 162-Amino-5-(2-ethylsulfamoyl-phenyl)-N-pyridin-4-yl-nicotinamide (“A108”)

Under argon atmosphere, a reaction vessel is charged with 100 mg2-amino-5-bromo-N-pyridin-4-yl-nicotinamide, 86 mgbis(pinacolate)diboron, 5 ml degassed N,N-dimethyl-formamide and 134 mgpotassium acetate and stirred at room temperature. The reaction vesselis charged with 27 mg(1,1′-bis(diphenyl-phosphino)-ferrocen)dichloropalladium(II) and stirredat 80° C. for 14 h. 108 mg 2-Bromo-N-ethyl-benzenesulfonamide, 27 mg(1,1′-bis(diphenylphosphino)-ferrocen)dichloro-palladium(II) and 200 μlwater are added to the solution. The reaction mixture stirred at 100° C.for 14 h, cooled to room temperature and evaporated. The product ispurified by chromatography. 8 mg “A108” are obtained; method 1: HPLC/MS:1.32 min, [M+H]=398;

¹H NMR (500 MHz, DMSO-d₆/TFA-d₁) δ [ppm] 8.95 (1 H, d, J 2.0), 8.73 (2H, d, J 7.3), 8.38 (1 H, d, J 2.1), 8.36 (2 H, d, J 7.3), 8.14 (1 H, d,J 7.9), 7.76 (1 H, t, J 7.5), 7.70 (1 H, t, J 7.7), 7.57 (1 H, d, J7.5), 2.85 (2 H, q, J 7.2), 1.01 (3 H, t, J 7.2).

IC₅₀ values of compounds according to the invention inhibiting TBK1 andIKKε

TBK1 IKKε TBK1 Compound enzyme assay enzyme assay cell assay No. IC₅₀[nM] IC₅₀ [nM] IC₅₀ [nM] “A1” 390 120 1100 “A2” 130 110 “A3” 120 150“A4” 400 4500 “A5” 120 10000 “A6” 67 1900 7800 “A7” 150 1800 “A8” 78 8303100 “A9” 430 660 3000 “A10” 1000 “A11” 770 540 9800 “A12” 8300 1000“A13” 4000 1900 “A14” 4200 1900 “A15” 670 2000 “A16” 240 110 9300 “A17”330 340 8100 “A18” 790 640 “A19” 1000 2800 “A20” 1200 610 “A21” 260 9107000 “A22” 690 2400 “A23” 7400 2200 “A24” 1200 890 “A25” 360 530 “A26”8200 5200 “A27” 810 2600 “A28” 1200 2900 “A29” 890 2400 “A30” 1600 1900“A31” 400 990 “A32” 250 600 “A33” 250 600 “A34” 280 740 “A35” 450 “A36”190 540 “A37” 1100 3200 “A38” 740 1500 “A39” 910 390 “A40” “A41” “A42”670 1700 “A43” 140 330 “A44” 240 420 “A45” 610 140 “A46” 120 240 “A47”330 380 “A48” “A49” 410 930 “A50” 320 “A51” 740 270 “A52” 630 “A53” 160510 “A54” 88 450 “A55” 390 “A56” 510 340 “A57” 410 3300 “A58” 370 1800“A59” 150 830 “A60” 230 300 “A61” 160 480

The following examples relate to medicaments:

EXAMPLE A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

The invention claimed is:
 1. Compounds of the formula I

in which: X denotes CH, R denotes Ar or Het, R¹ denotes furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,para-pyridyl, pyrimidyl, pyridazinyl, indolyl, isoindolyl,benzimid-azolyl, indazolyl, quinolyl, 1,3-benzodioxolyl,benzothiophenyl, benzofuranyl, imidazopyridyl or furo[3,2-b]pyridyl,each of which is unsubstituted or mono- or disubstituted by Hal, A, OR⁵,CN, COOA, COOH, CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl, biphenyl ornaphtyl, each of which is unsubstituted or mono-, di- or trisubstitutedby Hal, A, Het¹, (CH₂)_(n)OR⁵, (CH₂)_(n)N(R⁵)₂, NO₂, CN, (CH₂)_(n)COOR⁵,CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NR⁵COA, NHCOOA,NR⁵SO₂A, COR⁵, SO₂Het², SO₂N(R⁵)₂ and/or S(O)_(p)A, Het denotes furyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, pyridyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazole,pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl,quinolyl, 1,3-benzo-dioxolyl, benzothiophenyl, benzofuranyl orimidazopyridyl, each of which is unsubstituted or mono-, di- ortrisubstituted by A, COA, (CH₂)_(p)Het², OH, OA, Hal, (CH₂)_(p)N(R⁵)₂,NO₂, CN, (CH₂)_(p)COOR⁵, (CH₂)_(p)CON(R⁵)₂, NR⁵COA, (CH₂)_(p)COHet²and/or (CH₂)_(p)phenyl, Het¹ denotes furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, thiadiazole, pyridazinyl, pyrazinyl,each of which is unsubstituted or mono-, di- or trisubstituted by A, OH,OA, Hal, CN and/or (CH₂)_(p)COOR⁵, Het² denotes dihydropyrrolyl,pyrrolidinyl, tetrahydroimidazolyl, dihydropyrazolyl,tetrahydropyrazolyl, dihydropyridyl, tetrahydropyridyl, piperidinyl,morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl,[1,3]dioxolanyl, piperazinyl, each of which is unsubstituted ormonosubstituted by OH and/or A, A′ denotes unbranched or branched alkylhaving 1-6 C atoms, in which 1-7 H atoms may be replaced by F, A denotesunbranched or branched alkyl having 1-10 C atoms, in which one or twonon-adjacent CH and/or CH₂ groups may be replaced by N, O, S atomsand/or by —CH═CH— groups and/or in addition 1-7 H atoms may be replacedby F, R⁵ denotes H or unbranched or branched alkyl having 1-6 C atoms,in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Br or I, ndenotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3 or 4,and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 2. Compounds according toclaim 1, in which: R¹ denotes para-pyridyl, pyrimidyl, pyridazinyl orfuro[3,2-b]pyridyl, each of which is unsubstituted or monosubstituted byHal, A, OR⁵, COOA, COOH, CON(R⁵)₂ and/or NR⁵COA′, and pharmaceuticallyusable salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.
 3. Compounds according to claim 1, in which: Ardenotes phenyl, biphenyl or naphtyl, each of which is unsubstituted ormono-, di- or trisubstituted by A, Hal, Het¹, COR⁵, CON(R⁵)₂,CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA, (CH₂)_(n)N(R⁵)₂,(CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 4. Compounds according toclaim 2, in which: Ar denotes phenyl, biphenyl or naphtyl, each of whichis unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹, COR⁵,CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂,and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 5. Compounds according toclaim 1, in which: Het denotes thienyl, pyrazolyl, pyridyl, each ofwhich is unsubstituted or mono- or disubstituted by A, (CH₂)_(p)Het²,(CH₂)_(p)CON(R⁵)₂ and/or (CH₂)_(p)phenyl, and pharmaceutically usablesalts, tautomers and stereoisomers thereof, including mixtures thereofin all ratios.
 6. Compounds according to claim 2, in which: Het denotesthienyl, pyrazolyl, pyridyl, each of which is unsubstituted or mono- ordisubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 7.Compounds according to claim 3, in which: Het denotes thienyl,pyrazolyl, pyridyl, each of which is unsubstituted or mono- ordisubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 8.Compounds according to claim 1, in which: Het¹ denotes pyrazolyl orimidazolyl, each of which is unsubstituted or monosubstituted by A, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 9. Compounds according toclaim 2, in which: Het¹ denotes pyrazolyl or imidazolyl, each of whichis unsubstituted or monosubstituted by A, and pharmaceutically usablesalts, tautomers and stereoisomers thereof, including mixtures thereofin all ratios.
 10. Compounds according to claim 3, in which: Het¹denotes pyrazolyl or imidazolyl, each of which is unsubstituted ormonosubstituted by A, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 11.Compounds according to claim 4, in which: Het¹ denotes pyrazolyl orimidazolyl, each of which is unsubstituted or monosubstituted by A, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 12. Compounds according toclaim 1, in which: Het² denotes pyrrolidinyl, piperidinyl, morpholinyl,[1,3]dioxolanyl, piperazinyl, each of which is unsubstituted ormonosubstituted by OH and/or A, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 13. Compounds according to claim 2, in which: Het² denotespyrrolidinyl, piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl,each of which is unsubstituted or monosubstituted by OH and/or A, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 14. Compounds according toclaim 3, in which: Het² denotes pyrrolidinyl, piperidinyl, morpholinyl,[1,3]dioxolanyl, piperazinyl, each of which is unsubstituted ormonosubstituted by OH and/or A, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 15. Compounds according to claim 4, in which: Het² denotespyrrolidinyl, piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl,each of which is unsubstituted or monosubstituted by OH and/or A, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 16. Compounds according toclaim 5, in which: Het² denotes pyrrolidinyl, piperidinyl, morpholinyl,[1,3]dioxolanyl, piperazinyl, each of which is unsubstituted ormonosubstituted by OH and/or A, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 17. Compounds according to claim 1, in which: A denotesunbranched or branched alkyl having 1-6 C atoms, in which one or twonon-adjacent CH and/or CH₂ groups may be replaced by N and/or O atomsand/or in addition 1-7 H atoms may be replaced by F, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 18. Compounds according toclaim 2, in which: A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH2 groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 19.Compounds according to claim 3, in which: A denotes unbranched orbranched alkyl having 1-6 C atoms, in which one or two non-adjacent CHand/or CH₂ groups may be replaced by N and/or O atoms and/or in addition1-7 H atoms may be replaced by F, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 20. Compounds according to claim 4, in which: A denotesunbranched or branched alkyl having 1-6 C atoms, in which one or twonon-adjacent CH and/or CH₂ groups may be replaced by N and/or O atomsand/or in addition 1-7 H atoms may be replaced by F, andpharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 21. Compounds according toclaim 5, in which: A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, and pharmaceutically usable salts, tautomers andstereoisomers thereof, including mixtures thereof in all ratios. 22.Compounds according to claim 6, in which: A denotes unbranched orbranched alkyl having 1-6 C atoms, in which one or two non-adjacent CHand/or CH₂ groups may be replaced by N and/or O atoms and/or in addition1-7 H atoms may be replaced by F, and pharmaceutically usable salts,tautomers and stereoisomers thereof, including mixtures thereof in allratios.
 23. Compounds according to claim 1, in which: X denotes CH, Rdenotes Ar or Het, R¹ denotes para-pyridyl, pyrimidyl, pyridazinyl orfuro[3,2-b]pyridyl, each of which is unsubstituted or monosubstituted byHal, A, OR⁵, COOA, COOH, CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl,biphenyl or naphtyl, each of which is unsubstituted or mono-, di- ortrisubstituted by A, Hal, Het¹, COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′,CON[R⁵(CH₂)_(n)Het¹], NHCOOA, (CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵,(CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂, Het denotes thienyl,pyrazolyl, pyridyl, each of which is unsubstituted or mono- ordisubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, Het¹ denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A, Het² denotes pyrrolidinyl,piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which isunsubstituted or monosubstituted by OH and/or A, A′ denotes unbranchedor branched alkyl having 1-6 C atoms, in which 1-7 H atoms may bereplaced by F, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, R⁵ denotes H or unbranched or branched alkyl having 1-6 Catoms, in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Bror I, n denotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3or 4, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 24. Compoundsaccording to claim 2, in which: X denotes CH, R denotes Ar or Het, R¹denotes para-pyridyl, pyrimidyl, pyridazinyl or furo[3,2-b]pyridyl, eachof which is unsubstituted or monosubstituted by Hal, A, OR⁵, COOA, COOH,CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl, biphenyl or naphtyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂,Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstitutedor mono- or disubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, Het¹ denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A, Het² denotes pyrrolidinyl,piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which isunsubstituted or monosubstituted by OH and/or A, A′ denotes unbranchedor branched alkyl having 1-6 C atoms, in which 1-7 H atoms may bereplaced by F, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, R⁵ denotes H or unbranched or branched alkyl having 1-6 Catoms, in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Bror I, n denotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3or 4, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 25. Compoundsaccording to claim 3, in which: X denotes CH, R denotes Ar or Het, R¹denotes para-pyridyl, pyrimidyl, pyridazinyl or furo[3,2-b]pyridyl, eachof which is unsubstituted or monosubstituted by Hal, A, OR⁵, COOA, COOH,CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl, biphenyl or naphtyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂,Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstitutedor mono- or disubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, Het¹ denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A, Het² denotes pyrrolidinyl,piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which isunsubstituted or monosubstituted by OH and/or A, A′ denotes unbranchedor branched alkyl having 1-6 C atoms, in which 1-7 H atoms may bereplaced by F, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, R⁵ denotes H or unbranched or branched alkyl having 1-6 Catoms, in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Bror I, n denotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3or 4, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 26. Compoundsaccording to claim 4, in which: X denotes CH, R denotes Ar or Het, R¹denotes para-pyridyl, pyrimidyl, pyridazinyl or furo[3,2-b]pyridyl, eachof which is unsubstituted or monosubstituted by Hal, A, OR⁵, COOA, COOH,CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl, biphenyl or naphtyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂,Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstitutedor mono- or disubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, Het¹ denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A, Het² denotes pyrrolidinyl,piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which isunsubstituted or monosubstituted by OH and/or A, A′ denotes unbranchedor branched alkyl having 1-6 C atoms, in which 1-7 H atoms may bereplaced by F, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, R⁵ denotes H or unbranched or branched alkyl having 1-6 Catoms, in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Bror I, n denotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3or 4, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 27. Compoundsaccording to claim 5, in which: X denotes CH, R denotes Ar or Het, R¹denotes para-pyridyl, pyrimidyl, pyridazinyl or furo[3,2-b]pyridyl, eachof which is unsubstituted or monosubstituted by Hal, A, OR⁵, COOA, COOH,CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl, biphenyl or naphtyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂,Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstitutedor mono- or disubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, Het¹ denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A, Het² denotes pyrrolidinyl,piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which isunsubstituted or monosubstituted by OH and/or A, A′ denotes unbranchedor branched alkyl having 1-6 C atoms, in which 1-7 H atoms may bereplaced by F, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, R⁵ denotes H or unbranched or branched alkyl having 1-6 Catoms, in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Bror I, n denotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3or 4, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 28. Compoundsaccording to claim 6, in which: X denotes CH, R denotes Ar or Het, R¹denotes para-pyridyl, pyrimidyl, pyridazinyl or furo[3,2-b]pyridyl, eachof which is unsubstituted or monosubstituted by Hal, A, OR⁵, COOA, COOH,CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl, biphenyl or naphtyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂,Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstitutedor mono- or disubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, Het¹ denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A, Het² denotes pyrrolidinyl,piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which isunsubstituted or monosubstituted by OH and/or A, A′ denotes unbranchedor branched alkyl having 1-6 C atoms, in which 1-7 H atoms may bereplaced by F, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, R⁵ denotes H or unbranched or branched alkyl having 1-6 Catoms, in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Bror I, n denotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3or 4, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 29. Compoundsaccording to claim 7, in which: X denotes CH, R denotes Ar or Het, R¹denotes para-pyridyl, pyrimidyl, pyridazinyl or furo[3,2-b]pyridyl, eachof which is unsubstituted or monosubstituted by Hal, A, OR⁵, COOA, COOH,CON(R⁵)₂ and/or NR⁵COA′, Ar denotes phenyl, biphenyl or naphtyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted by A, Hal, Het¹,COR⁵, CON(R⁵)₂, CONH(CH₂)_(q)NHCOOA′, CON[R⁵(CH₂)_(n)Het¹], NHCOOA,(CH₂)_(n)N(R⁵)₂, (CH₂)_(n)OR⁵, (CH₂)_(n)COOR⁵, SO₂Het² and/or SO₂N(R⁵)₂,Het denotes thienyl, pyrazolyl, pyridyl, each of which is unsubstitutedor mono- or disubstituted by A, (CH₂)_(p)Het², (CH₂)_(p)CON(R⁵)₂ and/or(CH₂)_(p)phenyl, Het¹ denotes pyrazolyl or imidazolyl, each of which isunsubstituted or monosubstituted by A, Het² denotes pyrrolidinyl,piperidinyl, morpholinyl, [1,3]dioxolanyl, piperazinyl, each of which isunsubstituted or monosubstituted by OH and/or A, A′ denotes unbranchedor branched alkyl having 1-6 C atoms, in which 1-7 H atoms may bereplaced by F, A denotes unbranched or branched alkyl having 1-6 Catoms, in which one or two non-adjacent CH and/or CH₂ groups may bereplaced by N and/or O atoms and/or in addition 1-7 H atoms may bereplaced by F, R⁵ denotes H or unbranched or branched alkyl having 1-6 Catoms, in which 1-7 H atoms may be replaced by F, Hal denotes F, Cl, Bror I, n denotes 0, 1, 2, 3 or 4, p denotes 0, 1 or 2, q denotes 1, 2, 3or 4, and pharmaceutically usable salts, tautomers and stereoisomersthereof, including mixtures thereof in all ratios.
 30. Compoundsaccording to claim 1, selected from the group consisting of: compoundnr. name “A1”2-Amino-5-(5-piperidin-1-ylmethyl-thiophen-2-yl)-N-pyridin-4-yl-nicotinamide “A2”2-Amino-N-pyridin-4-yl-5-(5-pyrrolidin-1-ylmethyl-thiophen-2-yl)-nicotinamide “A3”2-Amino-5-(5-methyl-thiophen-2-yl)-N-pyridin-4-yl-nicotinamide “A4”2-Amino-5-(3-pyrazol-1-yl-phenyl)-N-pyridin-4-yl-nicotinamide “A5”2-Amino-5-(4-pyrazol-1-yl-phenyl)-N-pyridin-4-yl-nicotinamide “A6”2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamide “A7”2-Amino-N-pyridin-4-yl-5-(4-sulfamoyl-phenyl)-nicotinamide “A8”2-Amino-N-(2-methyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A9”2-Amino-N-(2-ethoxy-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A11”6-Amino-6′-piperazin-1-yl-[3,3′]bipyridinyl-5-carboxylic acid pyridin-4-ylamide “A15”2-Amino-N-(2-methyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thio-phen-3-yl)-nicotinamide “A16”2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-N-pyridazin-4-yl-nicotinamide “A17”2-Amino-5-(1-benzyl-1H-pyrazol-4-yl)-N-(2-methyl-pyridin-4-yl)-nicotinamide “A18”2-Amino-5-(3-pyrazol-1-yl-phenyl)-N-pyridazin-4-yl-nicotinamide “A19”2-Amino-N-(3-methyl-pyridin-4-yl)-5-(4-pyrazol-1-yl-phenyl)-nicotinamide “A20”2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-(2-methyl-pyridine-4-yl)-nicotinamide “A21”2-Amino-N-(3-methyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A22”2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-(3-methyl-pyridin-4-yl)-nicotinamide “A23”2-Amino-5-(4′-methyl-biphenyl-3-yl)-N-pyridin-4-yl-nicotinamide “A24”2-Amino-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-N-pyridazin-4-yl-nicotinamide “A25”2-Amino-5-(1-carbamoylmethyl-1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide “A26”2-Amino-N-(2,6-dimethyl-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A27”2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-N-pyrimidin-4-yl-nicotinamide “A28”2-Amino-N-furo[3,2-b]pyridin-7-yl-5-[1-(2-methoxy-ethyl)-1H-pyrazol-4-yl]-nicotinamide “A29”2-Amino-N-furo[3,2-b]pyridin-7-yl-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A30”4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoic acid methylester “A31” 4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-benzoicacid “A32”3-{4-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-phenyl}- propionicacid “A33” 2-Amino-N-(3-chloro-pyridin-4-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A34”2-Amino-5-(1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide “A35”4-{[2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-pyridine-3-carbonyl]-amino}-nicotinic acid methyl ester “A36”N-(2-Acetylamino-pyridin-4-yl)-2-amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A37”3-[6-Amino-5-(pyridin-4-ylcarbamoyl)-pyridin-2-yl]-benzoic acid “A38”2-Amino-N-(3-chloro-pyridin-4-yl)-5-[1-(2-methoxy-ethyl-)-1H-pyrazol-4-yl]nicotinamide “A39”2-Amino-N-(4-methoxy-phenyl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A40”2-Amino-N-(6-methoxy-pyridin-3-yl)-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-nicotinamide “A41”2-Amino-N-(3-methylcarbamoyl-pyridin-4-yl)-5-(5-morpholin-4-yl-methyl-thiophen-2-yl)-nicotinamide “A42”2-Amino-5-[1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamide “A43”2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-3-yl)-N-pyridin-4-yl-nicotinamide “A44”5-(4-Acetyl-1H-pyrrol-2-yl)-2-amino-N-pyridin-4-yl-nicotinamide “A45”2-Amino-5-furan-3-yl-N-pyridin-4-yl-nicotinamide “A46”2-Amino-5-(1-benzyl-1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide “A47”2-Amino-5-(1-methyl-1H-pyrazol-3-yl)-N-pyridin-4-yl-nicotinamide “A48”2-Amino-5-(3,5-dimethyl-1H-pyrazol-4-yl)-N-pyridin-4-yl- nicotinamide“A49” 2-Amino-N-pyridin-4-yl-5-thiophen-3-yl-nicotinamide “A50”2-Amino-5-(1-methyl-1H-pyrrol-2-yl)-N-pyridin-4-yl-nicotinamide “A51”2-Amino-5-[1-(2-morpholin-4-yl-ethyl)-1H-pyrazol-4-yl]-N-pyridin-4-yl-nicotinamide “A52”2-Amino-5-benzo[b]thiophen-2-yl-N-pyridin-4-yl-nicotinamide “A53”5-(5-Acetyl-thiophen-2-yl)-2-amino-N-pyridin-4-yl-nicotinamide “A54”2-Amino-5-(5-morpholin-4-ylmethyl-thiophen-2-yl)-N-pyridin-4-yl-nicotinamide “A55” 2-Amino-5-(1H-indol-2-yl)-N-pyridin-4-yl-nicotinamide“A56” 2-Amino-5-(1H-indol-3-yl)-N-pyridin-4-yl-nicotinamide “A57”2-Amino-N-pyridin-4-yl-5-(1H-pyrrol-2-yl)-nicotinamide “A58”2-Amino-5-(1H-imidazo[1,2-a]pyridin-2-yl)-N-pyridin-4-yl- nicotinamide“A59” 2-Amino-N-pyridin-4-yl-5-(1H-pyrrol-3-yl)-nicotinamide “A60”2-Amino-5-benzofuran-3-yl-N-pyridin-4-yl-nicotinamide “A61”2-Amino-5-(1-methyl-1H-pyrazol-4-yl)-N-pyridin-4-yl-nicotinamide

and pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 31. Process for thepreparation of compounds of the formula I according to claim 1 andpharmaceutically usable salts, tautomers and stereoisomers thereof,characterised in that: a) a compound of the formula II

in which Y denotes an Br or I, X and R¹ have the meanings indicated inclaim 1, is reacted with a compound of formula IIIR-L  III in which R has the meaning indicated in claim 1 and L denotes aboronic acid or a boronic acid ester group, or b) a compound of theformula IV

in which R and X have the meanings indicated in claim 1 and L¹ denotesCl, Br, I or a free or reactively functionally modified OH group, isreacted with a compound of the formula VR¹—NH₂  V in which R¹ has the meaning indicated in claim 1, or c) thatit is liberated from one of its functional derivatives by treatment witha solvolysing or hydrolysing agent, and/or a base or acid of the formulaI is converted into one of its salts.
 32. Medicaments comprising: i) acompound of the formula I according to claim 1 and ii) pharmaceuticallyusable salts, tautomers and stereoisomers thereof, including mixturesthereof in all ratios.
 33. A method for treating diseases selected fromthe group consisting of: cancer, septic shock, Primary open AngleGlaucoma (POAG), hyperplasia, rheumatoid arthritis, psoriasis,artherosclerosis, retinopathy, osteoarthritis, endometriosis, chronicinflammation, and neurodegenerative diseases comprising administeringcompounds of the formula I, according to claim 1, to a patientpresenting at least one symptom of said diseases.
 34. The method asclaimed in claim 33 wherein said compounds further comprise:pharmaceutically usable salts, tautomers and stereoisomers thereof,including mixtures thereof in all ratios.
 35. A method for the treatmentof tumours comprising administering to a patient having a tumour thecompounds of formula I according to claim 1 in combination with acompound from the group consisting of: oestrogen receptor modulator,androgen receptor modulator, retinoid receptor modulator, cytotoxicagent, antiproliferative agent, prenyl-protein transferase inhibitor,HMG-CoA reductase inhibitor, HIV protease inhibitor, reversetranscriptase inhibitor and angiogenesis inhibitors.
 36. A method forthe treatment of tumours comprising administering to a patient having atumour the compounds of formula I according to claim 1 in combinationwith radiotherapy and a compound from the group consisting of: oestrogenreceptor modulator, androgen receptor modulator, retinoid receptormodulator, cytotoxic agent, anti-proliferative agent, prenyl-proteintransferase inhibitor, HMG-CoA reductase inhibitor, HIV proteaseinhibitor, reverse transcriptase inhibitor and angiogenesis inhibitors.